S A Tailor, A K Gupta, S E Walker, N H Shear
Peripheral edema due to nifedipine-itraconazole interaction: a case report.
Arch Dermatol. 1996 Mar;132(3):350-2.
Abstract/Text
Jun Kato, Takehiko Mori, Yukinori Nakamura, Masatoshi Sakurai, Yoshinobu Aisa, Yasuo Ikeda, Shinichiro Okamoto
Hypotension due to the drug interaction of voriconazole with eplerenone and nifedipine.
Eur J Clin Pharmacol. 2009 Mar;65(3):323-4. doi: 10.1007/s00228-008-0588-1. Epub 2008 Nov 25.
Abstract/Text
K S Lown, J C Kolars, K E Thummel, J L Barnett, K L Kunze, S A Wrighton, P B Watkins
Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test.
Drug Metab Dispos. 1994 Nov-Dec;22(6):947-55.
Abstract/Text
The CYP3A subfamily of cytochromes P450 metabolize many medications and environmental contaminants. CYP3A4 and, in 25% of patients, CYP3A5 seem to be the major CYP3A genes expressed in adult liver. Hepatic levels of CYP3A4 can be estimated by the erythromycin breath test and vary at least 10-fold among patients. CYP3A4 has also been shown to be present in small bowel where it is responsible for significant "first-pass" metabolism of orally administered substrates. However, it is not known whether there is significant interindividual variability in the intestinal expression of CYP3A4, or whether the liver and intestinal catalytic activities of CYP3A4 correlate within an individual. It is also not known whether CYP3A5 is expressed in the small intestine. To address these questions, we administered the erythromycin breath test to 20 patients and obtained biopsies from their small bowel. There was a 6-fold variation in CYP3A catalytic activity (midazolam hydroxylation), an 11-fold variation in CYP3A4 protein content, and an 8-fold variation in CYP3A4 mRNA content in intestinal biopsies. There was an excellent correlation between intestinal CYP3A4 protein level and catalytic activity (r = 0.86; p = 0.0001); however, neither parameter significantly correlated with hepatic CYP3A4 activity as measured by the erythromycin breath test result (r = 0.27; p = 0.24 and r = 0.33; p = 0.15, respectively). We also found that CYP3A5 protein was readily detectable in biopsies from 14 (70%) of the patients, indicating that CYP3A5 is commonly expressed in human small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)
K S Lown, K E Thummel, P E Benedict, D D Shen, D K Turgeon, S Berent, P B Watkins
The erythromycin breath test predicts the clearance of midazolam.
Clin Pharmacol Ther. 1995 Jan;57(1):16-24. doi: 10.1016/0009-9236(95)90261-9.
Abstract/Text
Midazolam, a commonly used sedative and amnestic medication, has recently been shown to be largely metabolized in the liver by a cytochrome P450, termed CYP3A4. There is at least a tenfold intersubject variability in the liver content and catalytic activity of CYP3A4, which may in part account for the known interpatient differences in the kinetics of midazolam. To test this hypothesis, we determined the intravenous midazolam kinetics of 20 medically stable, hospitalized patients, whose hepatic CYP3A4 activities were determined with use of the [14C-N-methyl]erythromycin breath test. During the kinetic study, we also performed psychometric testing designed to quantitate the level of sedation and amnesia. We found a significant positive correlation between the erythromycin breath test results and weight adjusted clearance (in milliliters per minute per kilogram) of both total midazolam (r = 0.52; p = 0.03) and unbound midazolam (r = 0.61; p < 0.01). The relatively low dose of midazolam used (0.0145 mg/kg) produced significant but transient sedation and memory impairment in some of the patients. We conclude that interpatient differences in liver CYP3A4 activity in part account for the variations in midazolam kinetics. Our observations account for reported drug interactions involving midazolam and suggest that patients with low CYP3A4 activity may be most susceptible to prolonged amnestic effects occasionally produced by this short-acting benzodiazepine.
K M Jalava, K T Olkkola, P J Neuvonen
Itraconazole greatly increases plasma concentrations and effects of felodipine.
Clin Pharmacol Ther. 1997 Apr;61(4):410-5. doi: 10.1016/S0009-9236(97)90191-0.
Abstract/Text
BACKGROUND: Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized by CYP3A4. Itraconazole strongly interacts with some of the substrates of CYP3A4 (e.g., terfenadine, triazolam and lovastatin); hence it is important to uncover the possible interaction of itraconazole with felodipine.
METHODS: A double-blind, randomized, two-phase crossover design was used to investigate the interaction between felodipine and itraconazole. Nine healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each ingested a single 5 mg oral dose of felodipine. Plasma concentrations of felodipine and itraconazole were determined and systolic and diastolic blood pressures and heart rate were measured up to 32 hours.
RESULTS: On average, itraconazole increased the peak plasma concentration (Cmax) of felodipine nearly eightfold (p < 0.001), the areas under the felodipine concentration-time curve [AUC(0-32) and AUC(0-infinity)] about sixfold (p < 0.001), and the elimination half-life twofold (p < 0.05). In seven of the nine subjects, even the Cmax of felodipine was lower without itraconazole than the 32-hour concentrations during the itraconazole phase. The decreases in blood pressure and the increases in heart rate were significantly greater during the itraconazole phase than during the placebo phase.
CONCLUSIONS: Itraconazole greatly increases plasma concentrations and effects of oral felodipine. The inhibition of CYP3A4 during the first-pass and elimination phases of felodipine seems to be the mechanism of the observed interaction. The concomitant use of itraconazole and some other azole antifungals with felodipine and other dihydropyridine calcium antagonists should be avoided or their doses should be reduced accordingly.
Yoshiyuki Ohno, Akihiro Hisaka, Hiroshi Suzuki
General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs.
Clin Pharmacokinet. 2007;46(8):681-96. doi: 10.2165/00003088-200746080-00005.
Abstract/Text
BACKGROUND: Cytochrome P450 (CYP) 3A4 is the most prevalent metabolising enzyme in the human liver and is also a target for various drug interactions of significant clinical concern. Even though there are numerous reports regarding drug interactions involving CYP3A4, it is far from easy to estimate all potential interactions, since too many drugs are metabolised by CYP3A4. For this reason, a comprehensive framework for the prediction of CYP3A4-mediated drug interactions would be of considerable clinical importance.
OBJECTIVE: The objective of this study was to provide a robust and practical method for the prediction of drug interactions mediated by CYP3A4 using minimal in vivo information from drug-interaction studies, which are often carried out early in the course of drug development.
DATA SOURCES: The analysis was based on 113 drug-interaction studies reported in 78 published articles over the period 1983-2006. The articles were used if they contained sufficient information about drug interactions. Information on drug names, doses and the magnitude of the increase in the area under the concentration-time curve (AUC) were collected.
METHODS: The ratio of the contribution of CYP3A4 to oral clearance (CR(CYP)(3A4)) was calculated for 14 substrates (midazolam, alprazolam, buspirone, cerivastatin, atorvastatin, ciclosporin, felodipine, lovastatin, nifedipine, nisoldipine, simvastatin, triazolam, zolpidem and telithromycin) based on AUC increases observed in interaction studies with itraconazole or ketoconazole. Similarly, the time-averaged apparent inhibition ratio of CYP3A4 (IR(CYP)(3A4)) was calculated for 18 inhibitors (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, saquinavir, nefazodone, erythromycin, diltiazem, fluconazole, verapamil, cimetidine, ranitidine, roxithromycin, fluvoxamine, azithromycin, gatifloxacin and fluoxetine) primarily based on AUC increases observed in drug-interaction studies with midazolam. The increases in the AUC of a substrate associated with coadministration of an inhibitor were estimated using the equation 1/(1 - CR(CYP)(3A4) x IR(CYP)(3A4)), based on pharmacokinetic considerations.
RESULTS: The proposed method enabled predictions of the AUC increase by interactions with any combination of these substrates and inhibitors (total 251 matches). In order to validate the reliability of the method, the AUC increases in 60 additional studies were analysed. The method successfully predicted AUC increases within 67-150% of the observed increase for 50 studies (83%) and within 50-200% for 57 studies (95%). Midazolam is the most reliable standard substrate for evaluation of the in vivo inhibition of CYP3A4. The present analysis suggests that simvastatin, lovastatin and buspirone can be used as alternatives. To evaluate the in vivo contribution of CYP3A4, ketoconazole or itraconazole is the selective inhibitor of choice.
CONCLUSION: This method is applicable to (i) prioritize clinical trials for investigating drug interactions during the course of drug development and (ii) predict the clinical significance of unknown drug interactions. If a drug-interaction study is carefully designed using appropriate standard drugs, significant interactions involving CYP3A4 will not be missed. In addition, the extent of CYP3A4-mediated interactions between many other drugs can be predicted using the current method.
H Yoshimoto, M Takahashi, S Saima
[Influence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients].
Nihon Ronen Igakkai Zasshi. 1996 Sep;33(9):692-6.
Abstract/Text
Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.
J Drayton, G Dickinson, M G Rinaldi
Coadministration of rifampin and itraconazole leads to undetectable levels of serum itraconazole.
Clin Infect Dis. 1994 Feb;18(2):266.
Abstract/Text
M J Gooderham, P Bolli, P G Fernandez
Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin.
Ann Pharmacother. 1999 Jul-Aug;33(7-8):796-9.
Abstract/Text
OBJECTIVE: To report a case of a clarithromycin-associated warfarin interaction and digoxin toxicity in a patient.
CASE SUMMARY: A 72-year-old white woman with chronic atrial fibrillation receiving long-standing therapy with digoxin 0.25 mg/d and warfarin 22.5 mg/wk was prescribed clarithromycin 500 mg three times daily for eradication of Helicobacter pylori. The patient presented to the emergency department with gastrointestinal symptoms, weakness, dizziness, and visual changes 12 days after initiation of clarithromycin. Laboratory results revealed a serum digoxin concentration of 4.6 ng/mL (normal 1.0-2.6) and an international normalized ratio of 7.3 (2.0-3.0). Digoxin, warfarin, and clarithromycin were discontinued and the patient was admitted to the hospital for treatment to resolve the symptoms and to return laboratory values to a safe range. Reduced dosages of digoxin (0.125 mg/d) and warfarin (17.5 mg/wk) were restarted on day 7 of hospitalization. The patient was discharged on day 11 in good condition.
DISCUSSION: Several reports of clarithromycin-induced drug interactions with digoxin and with warfarin have been published. Previously, case reports of macrolide-associated interactions mainly involved erythromycin, but more recently have implicated clarithromycin. The interaction between clarithromycin and warfarin is thought to occur from an inhibition of the cytochrome P450 drug metabolizing system. Clarithromycin is thought to cause digoxin toxicity by an alteration of the digoxin-metabolizing gut flora, thereby causing an increase in the digoxin concentration in susceptible individuals. Drug interactions can occur by different mechanisms in the same patient.
CONCLUSIONS: Potential drug interactions can occur between commonly prescribed medications. It is important to monitor patients for symptoms and alterations in laboratory values to prevent not only serious complications, but also unnecessary hospitalizations.
B F Gage, C S Eby
The genetics of vitamin K antagonists.
Pharmacogenomics J. 2004;4(4):224-5. doi: 10.1038/sj.tpj.6500258.
Abstract/Text
J G Gillum, D S Israel, R E Polk
Pharmacokinetic drug interactions with antimicrobial agents.
Clin Pharmacokinet. 1993 Dec;25(6):450-82. doi: 10.2165/00003088-199325060-00005.
Abstract/Text
As new classes of antimicrobial drugs have become available, and new uses found for older drugs, pharmacokinetic drug interactions with antimicrobials have become more common. Macrolides, fluoroquinolones, rifamycins, azoles and other agents can interact adversely with commonly used drugs, usually by altering their hepatic metabolism. The mechanisms by which antimicrobial agents alter the biotransformation of other drugs is increasingly understood to reflect inhibition or induction of specific cytochrome P450 enzymes. Macrolides inhibit cytochrome P450IIIA4 (CYP3A4), which appears to be the most common metabolic enzyme in the human liver and is involved in the metabolism of many drugs, including cyclosporin, warfarin and terfenadine. Some quinolones preferentially inhibit CYP1A2, which is partially responsible for methylxanthine metabolism. Azoles appear to be broad spectrum inhibitors of cytochromes P450. Within each of these antibiotic classes, there is a rank order of inhibitory potency towards specific cytochrome P450 enzymes. By contrast, rifampicin (rifampin) and rifabutin induce several cytochromes P450, including CYP3A4, and hence can enhance the metabolism of many other drugs. By using in vitro preparations of human enzymes it is increasingly possible to predict those antibiotics that will adversely affect the metabolism of other drugs. In addition, between-patient variability in frequency of interaction may relate to differences in the activities of these enzymes. Although the mechanisms and scope of these interactions are becoming well characterised, the remaining challenge is how to best inform the clinician so that the undesirable consequences of interactions may be prevented.
B R Woldtvedt, C L Cahoon, L A Bradley, S J Miller
Possible increased anticoagulation effect of warfarin induced by azithromycin.
Ann Pharmacother. 1998 Feb;32(2):269-70.
Abstract/Text
H I Bussey, L C Knodel, D A Boyle
Warfarin-erythromycin interaction.
Arch Intern Med. 1985 Sep;145(9):1736-7.
Abstract/Text
Patricia A Howard, Edward F Ellerbeck, Kimberly K Engelman, Kelly L Patterson
The nature and frequency of potential warfarin drug interactions that increase the risk of bleeding in patients with atrial fibrillation.
Pharmacoepidemiol Drug Saf. 2002 Oct-Nov;11(7):569-76. doi: 10.1002/pds.748.
Abstract/Text
PURPOSE: To determine the frequency with which atrial fibrillation (AF) patients receiving warfarin are prescribed interacting drugs that could increase bleeding risks.
METHODS: We retrospectively examined medical records for 704 Medicare beneficiaries > or = 65 years of age discharged from Kansas hospitals with AF. We identified all patients receiving warfarin and examined discharge prescriptions for drugs that could increase bleeding risk either by increasing the international normalized ratio (INR) or directly inhibiting hemostasis.
RESULTS: Of 256 patients discharged on warfarin, 138 (54%) were prescribed another medication that could increase bleeding risk. Among these patients, 106 (41%) were discharged with a total of 150 prescriptions for drugs that could interact with warfarin to increase the INR. Antibiotics accounted for 67% of these prescriptions. Fifty-three patients (21%) received 56 prescriptions for drugs which could inhibit hemostasis. These were primarily antiplatelet drugs with 61% of the prescriptions for aspirin. Patients with coronary artery disease were more likely than others to be prescribed warfarin plus antiplatelet agents (OR = 2.80; p = 0.04). More than one interacting drug was prescribed for 20% of the patients.
CONCLUSIONS: AF patients discharged on warfarin were frequently prescribed concomitant medications that increase bleeding risks. These patients should be closely monitored and counseled to watch for signs of bleeding.
工藤龍彦, 内堀陽二, 渥美和彦, 沼尾嘉時, 三浦勇, 設楽正登ほか：抗凝固療法中の納豆によるワーファリン拮抗作用．医学のあゆみ 104: 36, 1978.
須田光明：クロレラはワーファリンの抗凝固作用を減弱する．日内会誌 82: 137, 1993.
奥村仙示, 廣瀬美和, 武田英二：ビタミンK高含有経腸栄養剤のワルファリン療法に及ぼす影響．栄養―評価と治療 25: 481, 2008.
斎木明子, 中村敏明, 政田幹夫：ワーファリン®服用患者におけるビタミンK含有製剤の投与指針．医薬ジャーナル 39: 186, 2003.
Kenneth Skov, Britt Falskov, Esther Agnete Jensen, Mikkel Helleberg Dorff
Supratheraputic rivaroxaban levels: A persistent drug-drug interaction after discontinuation of amiodarone.
Basic Clin Pharmacol Toxicol. 2020 Oct;127(4):351-353. doi: 10.1111/bcpt.13419. Epub 2020 May 4.
Abstract/Text
We report the case of an 88-year old woman referred for evaluation of increased INR. Surprisingly supratherapeutic levels of rivaroxaban was detected. Upon scrutiny of the patient's medical history, a drug-drug interaction between amiodarone and rivaroxaban persisting 3 weeks after cessation of amiodaron remains the prime suspect causing the clinical picture. Both INR and rivaroxaban levels returned to normal within 3 days of cessation of rivaroxaban. The case highlights that rivaroxaban, although highly variably, does affect INR. Furthermore, it highlights that the potential for DDIs involving amiodarone may persists for weeks or months after discontinuation. Amiodarone is predicted to increase rivaroxaban exposure, through inhibition of rivaroxaban elimination via CYP3A4 and P-gp. Elderly patients and patients with declining renal function are especially at risk of increased rivaroxaban exposure when a DDI with amiodarone occurs.
© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
Tammy J Bungard, R Neil Roberts
Carbamazepine Induction Impacting Apixaban Concentrations: A Case Report.
CJC Open. 2020 Sep;2(5):423-425. doi: 10.1016/j.cjco.2020.04.009. Epub 2020 May 1.
Abstract/Text
Avoidance of apixaban with carbamazepine (CBZ) is recommended owing to an anticipated reduction in apixaban concentration, although this drug interaction is poorly described. We report a case wherein apixaban concentration was measured before and 2 weeks after CBZ. Apixaban concentrations were substantially reduced; hence, the dose of apixaban was doubled alongside a small increase in CBZ. Subsequent apixaban concentrations were essentially unchanged. This extent of reduction in apixaban concentration appears to be related to the dose of CBZ, with the interaction occurring over 2-4 weeks. This combination should be avoided unless apixaban concentrations can be assessed using a calibrated assay.
© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.
S Hirata, S Izumi, T Furukubo, M Ota, M Fujita, T Yamakawa, I Hasegawa, H Ohtani, Y Sawada
Interactions between clarithromycin and digoxin in patients with end-stage renal disease.
Int J Clin Pharmacol Ther. 2005 Jan;43(1):30-6.
Abstract/Text
OBJECTIVE: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy.
CASE SUMMARY: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 +/- 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200-400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8-4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53-190 days after the administration of clarithromycin.
CONCLUSION: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin should be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly.
J Lindenbaum, D G Rund, V P Butler, D Tse-Eng, J R Saha
Inactivation of digoxin by the gut flora: reversal by antibiotic therapy.
N Engl J Med. 1981 Oct 1;305(14):789-94. doi: 10.1056/NEJM198110013051403.
Abstract/Text
In approximately 10 per cent of patients given digoxin, substantial conversion of the drug to cardioinactive, reduced metabolites (digoxin reduction products, or DRPs) occurs. The site and clinical importance of this conversion is unknown. In four normal volunteers taking digoxin daily for four weeks, urinary excretion of DRPs was greatest after a poorly absorbed tablet was ingested, and least after intravenous administration, Stool cultures from subjects known to make DRPs in vivo ("excretors") converted digoxin to DRPs; cultures from nonexcretors did not. Three excretors were given tablets for 22 to 29 days. A five-day course of erythromycin or tetracycline, administered after a base-line period of 10 to 17 days, markedly reduced or eliminated DRP excretion in urine and stool. Serum digoxin concentrations rose as much as twofold after antibiotics were given. We conclude that in some persons digoxin is inactivated by gastrointestinal bacteria. Changes in the enteric flora may markedly alter the state of digitalization.
D H Peters, S P Clissold
Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.
Drugs. 1992 Jul;44(1):117-64.
Abstract/Text
Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of erythromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneumoniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies--chelonae and--abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the microbiologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated. The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including beta-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections. Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithromycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater tolerability, principally by inducing fewer gastrointestinal disturbances.(ABSTRACT TRUNCATED AT 400 WORDS)
A Sutton, M A Pilot
Digoxin toxicity and erythromycin.
BMJ. 1989 Apr 22;298(6680):1101.
Abstract/Text
Y Tanigawara, N Okamura, M Hirai, M Yasuhara, K Ueda, N Kioka, T Komano, R Hori
Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1).
J Pharmacol Exp Ther. 1992 Nov;263(2):840-5.
Abstract/Text
This article represents the first evidence that the renal secretion of the commonly used drug, digoxin, is mediated by P-glycoprotein. In this study, it was demonstrated that digoxin is a substrate of P-glycoprotein, and the mechanism of a clinically important drug interaction, such as digoxin-quinidine, was elucidated. Human P-glycoprotein was expressed on the apical membrane of the porcine kidney epithelial cell line, LLC-PK1 by transfecting with human MDR1 cDNA. The expression and function of P-glycoprotein were confirmed by Southern and Western blotting, RNase protection assay, immunostaining and transporting activity for vinblastine. The transepithelial transport of [3H]digoxin was measured across the cell monolayers grown on microporous polycarbonate membrane filters. The transfectant cells exhibited markedly greater basal-to-apical transport and less apical-to-basal transport than the host cells, and the former was 8-fold greater than the latter. The augmented transepithelial transport resulted from the increased efflux from cells to apical side. This oriented transport was inhibited by the presence of 20 microM vinblastine, quinidine or verapamil. The rate of efflux to the apical side was 2-fold greater than that to the basal side. Quinidine inhibited the efflux to the apical side but did not affect transport into the basal side. These findings demonstrate that digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney other than organic cation and anion transport systems, and suggest a molecular mechanism for the renal tubular secretion of digoxin as well as clinically important digoxin-quinidine interaction via P-glycoprotein.
H Wakasugi, I Yano, T Ito, T Hashida, T Futami, R Nohara, S Sasayama, K Inui
Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein.
Clin Pharmacol Ther. 1998 Jul;64(1):123-8. doi: 10.1016/S0009-9236(98)90030-3.
Abstract/Text
We present a digoxin-clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 +/- 0.20; mean +/- SD). Because P-glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P-glycoprotein-mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P-glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration-dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P-glycoprotein-mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.
Jens Rengelshausen, Christoph Göggelmann, Jürgen Burhenne, Klaus-Dieter Riedel, Jochen Ludwig, Johanna Weiss, Gerd Mikus, Ingeborg Walter-Sack, Walter E Haefeli
Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction.
Br J Clin Pharmacol. 2003 Jul;56(1):32-8.
Abstract/Text
AIMS: A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.
METHODS: In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.
RESULTS: Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin.
CONCLUSIONS: Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.
M K Sachs, L M Blanchard, P J Green
Interaction of itraconazole and digoxin.
Clin Infect Dis. 1993 Mar;16(3):400-3.
Abstract/Text
A 69-year-old man who had been taking digoxin for 2.5 years developed an elevated serum concentration of digoxin in association with digoxin toxicity (characterized by nausea and vomiting) 9 days after the addition of itraconazole to his regimen for the treatment of sternal osteomyelitis. Coadministration of itraconazole resulted in a statistically significant increase in the half-life of digoxin that necessitated a reduction of the digoxin dose by almost 60%. We thus recommend that patients receiving itraconazole and digoxin concomitantly have serum levels of digoxin monitored frequently. In addition, these patients should be carefully questioned about nonspecific gastrointestinal symptoms, which may indicate early digoxin toxicity.
Reinhard Ding, Yorki Tayrouz, Klaus-Dieter Riedel, Jürgen Burhenne, Johanna Weiss, Gerd Mikus, Walter E Haefeli
Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers.
Clin Pharmacol Ther. 2004 Jul;76(1):73-84. doi: 10.1016/j.clpt.2004.02.008.
Abstract/Text
BACKGROUND: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo.
METHODS: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days. With the assumption that ritonavir steady state had been reached, 0.5 mg digoxin was given intravenously on day 3. Digoxin concentrations were determined in plasma and urine by radioimmunoassay, and plasma ritonavir concentrations were determined by liquid chromatography-tandem mass spectrometry. Digoxin kinetics was estimated by compartmental and noncompartmental analyses, by use of the area under the plasma concentration-time curve, and the corresponding digoxin amount excreted into urine was used for digoxin clearance calculations.
RESULTS: Ritonavir significantly (P <.01) increased digoxin area under the plasma concentration-time curve from time 0 to infinity by 86% and its volume of distribution by 77% and decreased nonrenal and renal digoxin clearance by 48% and 35%, respectively. Digoxin terminal half-life in plasma increased by 156% (P <.01).
CONCLUSION: This inhibition of renal digoxin clearance is likely caused by ritonavir inhibition of P-gp. Its extent is considerable and similar to the effect of other potent P-gp inhibitors on digoxin disposition such as quinidine. These findings may, therefore, indicate that the pharmacokinetics of P-gp substrates sharing the renal tubular elimination pathway will be affected when combined with therapeutic doses of ritonavir in antiretroviral treatment regimens. In addition and contrarily to quinidine, these data indicate that ritonavir promotes digoxin distribution in the body.
Basma Ricaurte, Amir Guirguis, Harris C Taylor, Don Zabriskie
Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity.
Ann Pharmacother. 2006 Apr;40(4):753-7. doi: 10.1345/aph.1G462. Epub 2006 Mar 14.
Abstract/Text
OBJECTIVE: To describe the fifth reported instance, as of February 15, 2006, of a severe interaction between simvastatin and amiodarone and hypothesize inhibition of CYP3A4 as the major mechanism.
CASE SUMMARY: A 72-year-old white man (178 cm, 77.2 kg) with diabetes mellitus, hyperlipidemia, hypertension, and mild azotemia was hospitalized on September 21, 2004, with thigh weakness, achiness, and dark urine for 7 days. Coronary artery bypass had been performed on July 7, 2004. Amiodarone 200 mg/day was started on July 10, and simvastatin 80 mg/day was initiated on August 13. Laboratory testing on the present admission included creatine kinase (CK) 19,620 U/L (reference range 60-224), blood urea nitrogen 50 mg/dL, creatinine 2.6 mg/dL, aspartate aminotransferase (AST) 912 U/L (30-60), alanine aminotransferase (ALT) 748 U/L (30-60), urine myoglobin 71,100 microg/L (<50), and serum myoglobin 13,877 microg/L (<110). Simvastatin and amiodarone were discontinued, and the patient was hydrated with forced alkaline diuresis. Thirteen days later, his CK was 323 U/L, creatinine 1.7 mg/dL, ALT 145 U/L, and AST 37 U/L.
DISCUSSION: Simvastatin is metabolized primarily by CYP3A4, and amiodarone is a recognized inhibitor of this enzyme. This may, therefore, account for the presumed drug interaction.
CONCLUSIONS: An objective causal assessment suggests that rhabdomyolysis, renal failure, and possibly hepatotoxicity were probably related to an amiodarone-simvastatin interaction.
U Martinowitz, J Rabinovich, D Goldfarb, A Many, H Bank
Interaction between warfarin sodium and amiodarone.
N Engl J Med. 1981 Mar 12;304(11):671-2. doi: 10.1056/NEJM198103123041116.
Abstract/Text
A Hamer, T Peter, W J Mandel, M M Scheinman, D Weiss
The potentiation of warfarin anticoagulation by amiodarone.
Circulation. 1982 May;65(5):1025-9.
Abstract/Text
The potentiation of the anticoagulant effect of sodium warfarin by amiodarone is reported in 10 patients. Amiodarone appears to augment the depression of vitamin K-dependent coagulation factors caused by warfarin by an uncertain mechanism, and may lead to serious bleeding. The maintenance dose of warfarin should be halved when amiodarone and warfarin are prescribed together.
S Almog, N Shafran, H Halkin, P Weiss, Z Farfel, U Martinowitz, H Bank
Mechanism of warfarin potentiation by amiodarone: dose--and concentration--dependent inhibition of warfarin elimination.
Eur J Clin Pharmacol. 1985;28(3):257-61.
Abstract/Text
Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.
E L Michalets
Update: clinically significant cytochrome P-450 drug interactions.
Pharmacotherapy. 1998 Jan-Feb;18(1):84-112.
Abstract/Text
Recent technologies have resulted in an explosion of information concerning the cytochrome P-450 isoenzymes and increased awareness of life-threatening interactions with such commonly prescribed drugs as cisapride and some antihistamines. Knowledge of the substrates, inhibitors, and inducers of these enzymes assists in predicting clinically significant drug interactions. In addition to inhibition and induction, microsomal drug metabolism is affected by genetic polymorphisms, age, nutrition, hepatic disease, and endogenous chemicals. Of the more than 30 human isoenzymes identified to date, the major ones responsible for drug metabolism include CYP3A4, CYP2D6, CYP1A2, and the CYP2C subfamily.
C J Matheny, M W Lamb, K R Brouwer, G M Pollack
Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation.
Pharmacotherapy. 2001 Jul;21(7):778-96.
Abstract/Text
P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of multidrug resistance in cancer, only recently has the role of P-gp expressed in normal tissues as a determinant of drug pharmacokinetics and pharmacodynamics been examined. P-glycoprotein is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues. Many marketed drugs inhibit P-gp function, and several compounds are under development as P-gp inhibitors. Similarly, numerous drugs can induce P-gp expression. While P-gp induction does not have a therapeutic role, P-gp inhibition is an attractive therapeutic approach to reverse multidrug resistance. Clinicians should recognize that P-gp induction or inhibition may have a substantial effect on the pharmacokinetics and pharmacodynamics of concomitantly administered drugs that are substrates for this transporter.
L D Heimark, L Wienkers, K Kunze, M Gibaldi, A C Eddy, W F Trager, R A O'Reilly, D A Goulart
The mechanism of the interaction between amiodarone and warfarin in humans.
Clin Pharmacol Ther. 1992 Apr;51(4):398-407.
Abstract/Text
Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)-warfarin to (R,S)-warfarin alcohol-1 and the oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P-450 primarily responsible for the conversion of (S)-warfarin to its major metabolite, (S)-7-hydroxywarfarin.
Weeranuj Yamreudeewong, Michael DeBisschop, Linda G Martin, Dennis L Lower
Potentially significant drug interactions of class III antiarrhythmic drugs.
Drug Saf. 2003;26(6):421-38.
Abstract/Text
Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin. Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug. Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions. Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism. Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide. It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism. Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically. If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.
Y Hayashi, U Ikeda, T Hashimoto, T Watanabe, T Mitsuhashi, K Shimada
Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia.
Pacing Clin Electrophysiol. 1999 Apr;22(4 Pt 1):672-4.
Abstract/Text
We report a 76-year-old woman who developed TdP ventricular tachycardia induced by combined use of clarithromycin and disopyramide. She had a history of myocardial infarction 5 years earlier and has taken disopyramide for supraventricular arrhythmias. In addition, she had taken clarithromycin for upper respiratory tract infection. On admission, an ECG showed prolongation of QTc interval to 0.71 seconds and self-terminating TdP occurred several times. Disopyramide was metabolized by the cytochrome enzyme CYP3A4 and clarithromycin competitively inhibits this enzyme, probably resulting in an increase in plasma concentration of disopyramide. We should consider this possibility when prescribing clarithromycin in combination with antiarrhythmic agent disopyramide.
千葉 寛：ヒト試料を用いた薬物相互作用の予測．薬物動態. 11: 294, 1996.
M F Segaert, C De Soete, I Vandewiele, J Verbanck
Drug-interaction-induced rhabdomyolysis.
Nephrol Dial Transplant. 1996 Sep;11(9):1846-7.
Abstract/Text
P J Neuvonen, T Kantola, K T Kivistö
Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole.
Clin Pharmacol Ther. 1998 Mar;63(3):332-41. doi: 10.1016/S0009-9236(98)90165-5.
Abstract/Text
BACKGROUND: Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin.
METHODS: Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined.
RESULTS: In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II.
CONCLUSIONS: Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced.
T Kantola, K T Kivistö, P J Neuvonen
Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.
Clin Pharmacol Ther. 1998 Aug;64(2):177-82. doi: 10.1016/S0009-9236(98)90151-5.
Abstract/Text
OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours.
RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil.
CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.
Hitoshi Ando, Shuichi Tsuruoka, Hayato Yanagihara, Koh-ichi Sugimoto, Masaaki Miyata, Yasushi Yamazoe, Toshinari Takamura, Shuichi Kaneko, Akio Fujimura
Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin.
Br J Clin Pharmacol. 2005 Nov;60(5):494-7. doi: 10.1111/j.1365-2125.2005.02462.x.
Abstract/Text
AIMS: To compare the effects of grapefruit juice (GFJ) on the pharmacokinetics of pitavastatin and atorvastatin.
METHODS: In a randomized, four-phase crossover study, eight healthy subjects consumed either GFJ or water t.i.d. for 4 days in each trial. On each final day, a single dose of 4 mg pitavastatin or 20 mg atorvastatin was administered.
RESULTS: GFJ increased the mean AUC(0-24) of atorvastatin acid by 83% (95% CI 23-144%) and that of pitavastatin acid by 13% (-3 to 29%).
CONCLUSIONS: Pitavastatin, unlike atorvastatin, appears to be scarcely affected by the CYP3A4-mediated metabolism.
大沢謙三, 小池伸彦, 篁俊成, 永井幸広, 小林健一：ベザフィブラート投与後に低血糖発作を生じたNIDDMの3症例．糖尿病. 37: 295, 1994.
R Smud, B Sermukslis
Bezafibrate and fenofibrate in type II diabetics with hyperlipoproteinaemia.
Curr Med Res Opin. 1987;10(9):612-24. doi: 10.1185/03007998709112415.
Abstract/Text
A double-blind study was carried out in 64 Type II diabetic patients, controlled with diet therapy and sulphonylureas (glibenclamide or chlorpropamide), who had associated hyperlipoproteinaemia which could not be normalized during a run-in period of 2 months by hygiene and dietary measures alone. The patients were allocated at random into 4 groups and each group was treated over 4 months with bezafibrate (600 mg/day) or fenofibrate (300 mg/day) in addition to their glibenclamide (5 to 15 mg/day) or chlorpropamide (250 to 500 mg/day) therapy plus diet. The results of monthly laboratory investigations showed that both hypolipaemic agents produced significant reductions in serum triglycerides, total cholesterol and LDL cholesterol and an increase in HDL cholesterol. There was a significantly greater increase in HDL cholesterol in patients treated with bezafibrate and glibenclamide, particularly in women, and greater control of blood glucose in those on bezafibrate. Both hypolipaemic drugs were well tolerated. Slight increases were recorded in serum transaminases in fenofibrate patients and in bleeding time in bezafibrate patients. It is concluded that, because of its greater effect on blood glucose and HDL cholesterol, the combination of bezafibrate with glibenclamide would appear to be the best of the regimens studied for the treatment of non-insulin-dependent diabetics with associated hyperlipoproteinaemia.
Lucia Micheli, Marcello Sbrilli, Cristina Nencini
Severe hypoglycemia associated with levofloxacin in Type 2 diabetic patients receiving polytherapy: two case reports.
Int J Clin Pharmacol Ther. 2012 Apr;50(4):302-6.
Abstract/Text
OBJECTIVE: Although hypoglycemia is known to be associated with levofloxacin, patients are continually being hospitalized because of this adverse event. Here we have reported two further cases of severe hypoglycemia and discussed the possibility that the hypoglycemia is the result of interactions between levofloxacin and certain drugs, in order to alert physicians to be aware that geriatric patients, particularly those with Type 2 diabetes and in polytherapy, are at risk of showing this adverse reaction. CASES SUMMARY: A 91-year-old woman with Type 2 diabetes on metformin and glibenclamide, also under treatment with oral antihypertensive drugs, platelet antiaggregant, low-molecular- weight heparin and buprenorphine, was prescribed levofloxacin for a bacterial infection. Liver function and renal function parameters were within normal limits. After repeated administration of levofloxacin, her serum glycemic levels had decreased to 47 mg/dl and the patient was in a coma. After stopping levofloxacin her glycemia level returned to the normal value. A 61 year-old male, affected by tonsillar squamous cell carcinoma, with Type 2 diabetes on metformin and glibenclamide, under treatment with low-molecular-weight heparin for deep venous thrombosis, hydromorphone and undergoing nutritional support, was treated with levofloxacin for a bacterial infection. After 72 h the patient was unresponsive and his blood glucose levels were 38 mg/dl. After discontinuation of levofloxacin administration the patient was treated with glucose infusion and his glycemic values gradually returned to the normal range.
DISCUSSION: The causality relationship between the levofloxacin and the hypoglycemia was established using Naranjo's ADR probability scale. These case reports confirm the literature data that serious hypoglycemia may develop due to the use of levofloxacin and appears to occur most frequently in elderly patients with Type 2 diabetes who are receiving oral hypoglycemic agents. We described the possible pharmacokinetic and pharmacodinamic mechanisms of the interaction between levofloxacin and the other drugs.
CONCLUSIONS: We hypothesized that the concomitant use of several drugs and particularly levofloxacin in association with oral antidiabetic drugs, opioid analgesics and low-molecular-weight heparin could concur to cause this side effect. The safety and tolerability of this anti-infective agent should be revised urgently.
N Maeda, T Tamagawa, I Niki, H Miura, K Ozawa, G Watanabe, K Nonogaki, K Uemura, A Iguchi
Increase in insulin release from rat pancreatic islets by quinolone antibiotics.
Br J Pharmacol. 1996 Jan;117(2):372-6.
Abstract/Text
1. The present study was undertaken to elucidate the mechanism(s) of hypoglycaemia caused by quinolone antibiotics. We investigated the effects of various quinolone antibiotics on insulin release in rat pancreatic islets. 2. At a non-stimulatory concentration of 3 mM glucose, lomefloxacin (LFLX) or sparfloxacin at 1 mM and pipemidic acid (0.1-1 mM) induced slight insulin release but tosufloxacin or enoxacin up to 100 microM did not. 3. At the stimulatory concentration of 10 mM glucose, all quinolones augmented insulin release in a dose-dependent manner. LFLX (100 microM) shifted the dose-response curve of glucose-induced insulin release to the left without altering the maximal response. 4. At 10 mM glucose, LFLX (100 microM) increased insulin release augmented by forskolin (5 microM) or 12-O-tetradecanoyl phorbol-13-acetate (100 nM) but not by raising the K+ concentration from 6 to 25 mM. 5. Verapamil (50 microM) or diazoxide (50-400 microM) antagonized the insulinotropic effect of LFLX. 6. These data suggest that quinolone antibiotics may cause hypoglycaemia by increasing insulin release via blockade of ATP-sensitive K+ channels.
Atsunori Saraya, Masaaki Yokokura, Tohru Gonoi, Susumu Seino
Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels.
Eur J Pharmacol. 2004 Aug 16;497(1):111-7. doi: 10.1016/j.ejphar.2004.06.032.
Abstract/Text
Although fluoroquinolones are used widely in the treatment of various infectious diseases, some of the drugs are known to cause hypoglycemia as a side-effect. We have investigated the effects of three fluoroquinolone derivatives, levofloxacin, gatifloxacin, and temafloxacin, on insulin secretion and pancreatic beta-cell ATP-sensitive K(+) channel (K(ATP) channel) activity. While levofloxacin had only a small effect on insulin secretion and K(ATP) currents, gatifloxacin and temafloxacin stimulated insulin secretion and inhibited K(ATP) channel currents in a dose-dependent manner. We also determined the site of action of gatifloxacin and temafloxacin on the K(ATP) channel. In a reconstituted system, gatifloxacin and temafloxacin inhibited Kir6.2 Delta C26 channels, which function in the absence of the SUR subunit, indicating direct action of the drugs on the Kir6.2 subunits. These results suggest that stimulation of insulin secretion by inhibition of pancreatic beta-cell K(ATP) channels underlies the hypoglycemia caused by certain fluoroquinolones.
Seth M Garber, Melanie W Pound, Susan M Miller
Hypoglycemia associated with the use of levofloxacin.
Am J Health Syst Pharm. 2009 Jun 1;66(11):1014-9. doi: 10.2146/ajhp080105.
Abstract/Text
PURPOSE: A case of hypoglycemia associated with levofloxacin is reported.
SUMMARY: A 58-year-old Caucasian man was admitted to the hospital for a heart failure (HF) exacerbation with suspected community-acquired pneumonia (CAP). His medical history included HF (left ventricular ejection fraction, 25-35%), hypertension, and type 2 diabetes mellitus. Renal insufficiency was noted during hospitalization, with a serum creatinine concentration of 1.5 mg/dL. The patient's only home medication was a self-reported "sugar pill," later identified as glimepiride. A chest radiograph revealed consolidation in both lung bases and bilateral pleural effusions. Levofloxacin 750 mg was administered orally on hospital day 1 for the treatment of CAP and was ordered to be administered every 48 hours. On hospital day 3, glipizide 10 mg was administered with a sliding-scale regimen of regular insulin in preparation for discharge. On hospital day 4, glipizide 10 mg was given again with the second dose of levofloxacin, 65 hours after the first levofloxacin dose was administered. The patient also received furosemide 40 mg orally twice daily, lisinopril 20 mg orally daily, and metoprolol 25 mg twice daily. The patient was discharged on hospital day 4 and returned to the emergency department early the next morning with a serum glucose concentration of 20 mg/dL. An i.v. infusion of 10% dextrose injection and three ampules of 50% dextrose injection were given to correct his hypoglycemia. Further glipizide doses were not administered.
CONCLUSION: A malnourished 58-year-old man with diabetes developed hypoglycemia after receiving levofloxacin in conjunction with glipizide.
梅木茂宣, 玉垣学也：レボフロキサシン投与にて高度低血糖発作を起こし、その後32 日間降血糖療法を要しなかった糖尿病症例．綜合臨床 2007；56：3315.
Trisha M Parekh, Mukaila Raji, Yu-Li Lin, Alai Tan, Yong-Fang Kuo, James S Goodwin
Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas.
JAMA Intern Med. 2014 Oct;174(10):1605-12. doi: 10.1001/jamainternmed.2014.3293.
Abstract/Text
IMPORTANCE: Certain antimicrobial drugs interact with sulfonylureas to increase the risk of hypoglycemia.
OBJECTIVE: To determine the risk of hypoglycemia and associated costs in older patients prescribed glipizide or glyburide who fill a prescription for an antimicrobial drug.
DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of Texas Medicare claims from 2006 to 2009 for patients 66 years or older who were prescribed glipizide or glyburide and who also filled a prescription for 1 of the 16 antimicrobials most commonly prescribed for this population.
METHODS: We assessed hypoglycemia events and associated Medicare costs in patients prescribed 1 of 7 antimicrobial agents thought to interact with sulfonylureas, using noninteracting antimicrobials as a comparison. We used a repeated measure logistic regression, controlling for age, sex, ethnicity, Medicaid eligibility, comorbidity, prior emergency department visits for hypoglycemia, prior hospitalizations for any cause, nursing home residence, and indication for the antimicrobial. We estimated odds of hypoglycemia, number needed to harm, deaths during hospitalization for hypoglycemia, and Medicare costs for hypoglycemia treatment.
MAIN OUTCOMES AND MEASURES: Any hospitalization or emergency department visit owing to hypoglycemia within 14 days of antimicrobial exposure.
RESULTS: In multivariable analyses controlling for patient characteristics and indication for antimicrobial drug use, clarithromycin (odds ratio [OR], 3.96 [95% CI, 2.42-6.49]), levofloxacin (OR, 2.60 [95% CI, 2.18-3.10]), sulfamethoxazole-trimethoprim (OR, 2.56 [95% CI, 2.12-3.10]), metronidazole (OR, 2.11 [95% CI, 1.28-3.47]), and ciprofloxacin (OR, 1.62 [95% CI, 1.33-1.97]) were associated with higher rates of hypoglycemia compared with a panel of noninteracting antimicrobials. The number needed to harm ranged from 71 for clarithromycin to 334 for ciprofloxacin. Patient factors associated with hypoglycemia included older age, female sex, black or Hispanic race/ethnicity, higher comorbidity, and prior hypoglycemic episode. In 2009, 28.3% of patients prescribed a sulfonylurea filled a prescription for 1 of these 5 antimicrobials, which were associated with 13.2% of all hypoglycemia events in patients taking sulfonylureas. The treatment of subsequent hypoglycemia adds $30.54 in additional Medicare costs to each prescription of 1 of those 5 antimicrobials given to patients taking sulfonylureas.
CONCLUSIONS AND RELEVANCE: Prescription of interacting antimicrobial drugs to patients on sulfonylureas is very common, and is associated with substantial morbidity and increased costs.
B Paidipaty, S Erickson
Ciprofloxacin-theophylline drug interaction.
Crit Care Med. 1990 Jun;18(6):685-6.
Abstract/Text
A M van den Brekel, L Harrington
Toxic effects of theophylline caused by fluvoxamine.
CMAJ. 1994 Nov 1;151(9):1289-90.
Abstract/Text
二木芳人, 吉田耕一郎：Garenoxacinとtheophyllineとの併用試験．日化療会誌. 55: 206, 2007.
Gabrielli A, Leoni P, Danieli G.: Methotrexate and non-steroidal anti-inflammatory drugs. Br J Med. 294: 776, 1987.
J R Brouwers, P A de Smet
Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs.
Clin Pharmacokinet. 1994 Dec;27(6):462-85. doi: 10.2165/00003088-199427060-00005.
Abstract/Text
The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible. Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption. Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values > 7. Histamine H2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined. More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window are most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID. Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous. Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment. Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made. When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved.
S Masuda, H Saito, K I Inui
Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1.
J Pharmacol Exp Ther. 1997 Dec;283(3):1039-42.
Abstract/Text
We recently cloned and characterized the rat kidney-specific organic anion transporter, OAT-K1, which was suggested to mediate renal tubular transport of methotrexate. In this study, we investigated the interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) with OAT-K1 by evaluating the effects of these drugs on renal distribution of methotrexate in vivo, and on methotrexate accumulation in the stably transfected LLC-PK1 cells expressing OAT-K1 (LLC-OAT-K1). NSAIDs such as indomethacin and ketoprofen had significant inhibitory effects on renal accumulation of methotrexate in rats after coadministration. Indomethacin and ketoprofen inhibited methotrexate accumulation by LLC-OAT-K1 cells in a competitive manner with the apparent inhibition constant values of 1. 0 mM and 1.9 mM, respectively. Other NSAIDs including ibuprofen, flufenamate and phenylbutazone also showed potent inhibitory effects on methotrexate accumulation. However, indomethacin was not transported via OAT-K1. These results indicate that NSAIDs have potent inhibitory effects against the OAT-K1-mediated methotrexate transport, which suggests that the OAT-K1 may be one of interaction sites for methotrexate and NSAIDs in the kidney.
Yuichi Uwai, Risa Taniguchi, Hideyuki Motohashi, Hideyuki Saito, Masahiro Okuda, Ken-ichi Inui
Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3.
Drug Metab Pharmacokinet. 2004 Oct;19(5):369-74.
Abstract/Text
Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.
Yoshitane Nozaki, Hiroyuki Kusuhara, Tsunenori Kondo, Masahiro Iwaki, Yoshiyuki Shiroyanagi, Hideki Nakayama, Shigeru Horita, Hayakazu Nakazawa, Teruo Okano, Yuichi Sugiyama
Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices.
J Pharmacol Exp Ther. 2007 Sep;322(3):1162-70. doi: 10.1124/jpet.107.121491. Epub 2007 Jun 19.
Abstract/Text
Simultaneous use of nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and other drugs has been reported to delay the plasma elimination of methotrexate in patients. Previously, we have reported that inhibition of the uptake process cannot explain such drug-drug interactions using rats. The present study quantitatively evaluated the possible role of the transporters in such drug-drug interactions using human kidney slices and membrane vesicles expressing human ATP-binding cassette (ABC) transporters. The uptake of methotrexate by human kidney slices was saturable with a K(m) of 45 to 49 microM. Saturable uptake of methotrexate by human kidney slices was markedly inhibited by p-aminohippurate and benzylpenicillin, but only weakly by 5-methyltetrahydrofolate. These transport characteristics are similar to those of a basolateral organic anion transporter (OAT) 3/SLC22A8. NSAIDs and probenecid inhibited the uptake of methotrexate by human kidney slices, and, in particular, salicylate, indomethacin, phenylbutazone, and probenecid were predicted to exhibit significant inhibition at clinically observed plasma concentrations. Among ABC transporters, such as BCRP/ABCG2, multidrug resistance-associated protein (MRP) 2/ABCC2, and MRP4/ABCC4, which are candidates for the luminal efflux of methotrexate, ATP-dependent uptake of methotrexate by MRP4-expressing membrane vesicles was most potently inhibited by NSAIDs. Salicylate and indomethacin were predicted to inhibit MRP4 at clinical plasma concentrations. Diclofenac-glucuronide significantly inhibited MRP2-mediated transport of methotrexate in a concentration-dependent manner, whereas naproxen-glucuronide had no effect. Inhibition of renal uptake (via OAT3) and efflux processes (via MRP2 and MRP4) explains the possible sites of drug-drug interaction for methotrexate with probenecid and some NSAIDs, including their glucuronides.
Azza A K El-Sheikh, Jeroen J M W van den Heuvel, Jan B Koenderink, Frans G M Russel
Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport.
J Pharmacol Exp Ther. 2007 Jan;320(1):229-35. doi: 10.1124/jpet.106.110379. Epub 2006 Sep 27.
Abstract/Text
Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimination. It has been shown that the mechanism of this interaction cannot be fully attributed to inhibition of basolateral MTX uptake in renal proximal tubules. Here, we studied the effect of various NSAIDs on MTX transport in membrane vesicles isolated from cells overexpressing the proximal tubular apical efflux transporters human multidrug resistance protein (MRP) 2/ABCC2 and MRP4/ABCC4. MTX was transported by MRP2 and MRP4 with Km values of 480 +/- 90 and 220 +/- 70 microM, respectively. The inhibitory potency of the NSAIDs was generally higher against MRP4- than MRP2-mediated MTX transport, with therapeutically relevant IC50 values, ranging from approximately 2 microM to 1.8 mM. Salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, and etodolac inhibited MRP2- and MRP4-mediated MTX transport according to a one-site competition model. In some cases, more complex interaction patterns were observed. Inhibition of MRP4 by diclofenac and MRP2 by indomethacin and ketoprofen followed a two-site competition model. Phenylbutazone stimulated MRP2 and celecoxib MRP4 transport at low concentrations and inhibited both transporters at high concentration. Our data suggest that the inhibition by NSAIDs of renal MTX efflux via MRP2 and MRP4 is a potential new site and mechanism contributing to the overall interaction between these drugs.
C F Stewart, R A Fleming, B F Germain, M J Seleznick, W E Evans
Aspirin alters methotrexate disposition in rheumatoid arthritis patients.
Arthritis Rheum. 1991 Dec;34(12):1514-20.
Abstract/Text
Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis.
J M Kremer, R A Hamilton
The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg.
J Rheumatol. 1995 Nov;22(11):2072-7.
Abstract/Text
OBJECTIVE: To determine the pharmacokinetics of methotrexate (MTX) with and without nonsteroidal antiinflammatory drugs (NSAID) at a 7.5 mg dose and higher usual maintenance doses of the drug. To determine the difference in pharmacokinetic variables when salicylate and nonsalicylate NSAID are administered with MTX at these doses.
METHODS: Thirty patients receiving MTX chronically underwent a study of MTX pharmacokinetics after 7.5 mg doses of MTX with their usual NSAID and after the NSAID were withheld for 5 half-lives. Sixteen additional patients underwent pharmacokinetics studies with and without NSAID while receiving their usual weekly maintenance dose of MTX of 16.6 (3.6) mg (Mean +/- SD).
RESULTS: No significant differences in pharmacokinetic variables were observed with and without NSAID at the 7.5 mg weekly dose of MTX. When patients received usual maintenance doses of MTX the renal clearance of MTX NSAID was 91.7 (26.4) ml/min versus 115.3 (34.4) ml/min without NSAID (p = 0.004). Creatinine clearance in patients taking usual maintenance doses increased from 77.5 (13.9) ml/min with NSAID to 95.3 (26.3) ml/min without NSAID (p = 0.05). A reduction in renal clearance of MTX was observed with maintenance dose MTX in both the 4 patients taking salicylates (p = 0.016) and the 12 patients taking nonsalicylate NSAID (p = 0.024).
CONCLUSION: NSAID produce significant decreases in renal clearance of MTX and creatinine when patients consume their usual weekly dose of the drug, but not when they take a 7.5 mg dose. This effect is likely to achieve clinical relevance across the dose ranges used to treat patients with rheumatoid arthritis.
厚生省薬務局：ニューキノロン系抗菌薬と非ステロイド性消炎鎮痛剤との相互作用（痙攣）．医薬品副作用情報 No 98. 1989.
山下武廣, 首藤寛, 佐藤勝彦, 西村清文, 藤田洽介, 杉元紘一：ニューキノロン系抗菌剤と非ステロイド性消炎鎮痛剤の併用により誘発された痙攣発作の2症例．ICUとCCU. 14: 877, 1990.
堀誠治, 島田甚五郎, 宮原正, 栗岡晋, 松田誠：キノロン系化学療法剤のけいれん発現機序に関する研究．神経化学. 26: 178, 1987.
N Akaike, T Shirasaki, T Yakushiji
Quinolones and fenbufen interact with GABAA receptor in dissociated hippocampal cells of rat.
J Neurophysiol. 1991 Aug;66(2):497-504.
Abstract/Text
1. Interaction of quinolone antibiotics and the anti-inflammatory agent fenbufen with the gamma-aminobutyric acid-A (GABAA) receptor-chloride channel complex in pyramidal neurons freshly dissociated from the hippocampal CA1 region of the rats was investigated in whole-cell mode, using the patch-clamp technique under voltage-clamp conditions. 2. Quinolones in clinical doses had no effects on the GABA-gated Cl- current (ICl) but slightly suppressed the response at concentrations greater than 10(-5) M. A metabolite of fenbufen, 4-biphenylacetic acid (BPA), also had little effect on the GABA response at therapeutic concentrations. 3. Coadministration of one of quinolones and BPA suppressed the GABA-gated ICl with increase in each of them in a concentration-dependent manner, and there was a parallel shift of the concentration-response curve for GABA to the right but with no effect on the maximum response, thereby indicating a competitive antagonism. The inhibitory potency of antibiotics in combination with BPA was in the order of norfloxacin much greater than enoxacin greater than cyprofloxacin greater than pipemidic acid much greater than ofloxacin greater than cinoxacin = piromidic acid = nalidixic acid = 0. 4. Norfloxacin and BPA, administered simultaneously, also strongly suppressed pentobarbital sodium (PB)-gated ICl, but they did not act on benzodiazepine (BZP) receptors. 5. Both GABA- and PB-induced ICls reversed at the Cl- equilibrium potential (ECl). In the presence of BPA, the quinolone-induced inhibition of GABA-gated ICls showed no voltage dependence. 6. It was concluded that, in the presence of an anti-inflammatory agent, the quinolone antibiotics decrease the affinity of GABAA receptors, the result being induction of epileptogenic neurotoxicities.
Seiji Hori, Junko Kizu, Masahiro Kawamura
Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs.
J Infect Chemother. 2003 Dec;9(4):314-20. doi: 10.1007/s10156-003-0275-1.
Abstract/Text
Quinolones have been reported to possess potent convulsant activity, which is enhanced when they are administered concurrently with anti-inflammatory drugs. To define the individual drug interactions of quinolones with anti-inflammatory drugs, we studied the convulsant activity of six quinolones with or without 13 anti-inflammatory drugs and 3 analgesic/antipyretic drugs in mice. Intraventricular injections of norfloxacin (NFLX), enoxacin (ENX), ciprofloxacin, lomefloxacin (LFLX), levofloxacin, and gatifloxacin induced convulsions in mice in a dose-dependent manner. Concurrent administration of biphenylacetic acid strongly enhanced the convulsant activity of NFLX, ENX, and LFLX. Flurbiprofen also strongly enhanced the activity of NFLX and ENX, and ketoprofen strongly enhanced the activity of ENX. However, mefenamic acid, piroxicam, tenoxicam, meloxicam, etodolac, sulpyrine, isopropylantipyrine, and acetaminophen had no effect on the convulsant activity of quinolones. These results suggest that each quinolone has an individual drug interaction with each anti-inflammatory drug. It was suggested that we should know which anti-inflammatory drugs enhance the convulsant activity of individual quinolones, and which quinolone has no/weak drug interaction with different anti-inflammatory drugs when these drugs are used concurrently for the treatment of patients with infectious diseases.
野崎正勝：薬物間相互作用の基礎と臨床 処方時にチェックの必要な組合わせの実際例 ニューキノロン薬と非ステロイド系抗炎症薬の併用によるけいれん．治療. 76: 2265, 1994.
J M Pochet, Y Pirson
Cyclosporin-diltiazem interaction.
Lancet. 1986 Apr 26;1(8487):979.
Abstract/Text
D Capone, G Tarantino, A Gentile, M Sabbatini, G Polichetti, M Santangelo, R Nappi, A Ciotola, V D'Alessandro, A Renda, V Basile, S Federico
Effects of voriconazole on tacrolimus metabolism in a kidney transplant recipient.
J Clin Pharm Ther. 2010 Feb;35(1):121-4. doi: 10.1111/j.1365-2710.2009.01070.x.
Abstract/Text
Infection occurs frequently in the organ transplant recipients during the post-transplant period because of immunosuppression. Therefore, prophylactic antimicrobial agents are often used. The azole antifungals, widely prescribed prophylactically, are known to have many drug-drug interactions. This report presents a case of drug-drug interaction between voriconazole and tacrolimus in a kidney transplant recipient. Voriconazole treatment led to a dramatic increase in tacrolimus concentration that required its discontinuation in spite of the manufacturer's guidelines that recommend a reduction of tacrolimus dosage by one-third. The present drug-drug interaction can be attributed to a strong inhibitory effect on cytochrome P450-3A4 activity by voriconazole. When voriconazole and tacrolimus are coadministered, close monitoring of tacrolimus blood levels is recommended as the rule-of-thumb reduction of tacrolimus dose by one-third may not be satisfactory.
M R First, J F Neylan, L L Rocher, A Tejani
Hypertension after renal transplantation.
J Am Soc Nephrol. 1994 Feb;4(8 Suppl):S30-6.
Abstract/Text
Hypertension is a frequent complication after organ transplantation in both children and adults and is a significant risk factor for the development of cardiovascular disease and graft dysfunction. There are multiple mechanisms responsible for the development of posttransplant hypertension. In the precyclosporine era, chronic rejection was the most common cause. The introduction of cyclosporine A has increased the prevalence of hypertension in solid organ transplant recipients. Cyclosporine increases renal vascular resistance by causing vasoconstriction of the afferent arteriole. From a pathophysiologic point of view, a calcium channel blocker should be used as the initial therapy in patients with cyclosporine-associated hypertension. Hypertension needs to be treated aggressively in all transplant recipients in an attempt to minimize allograft and cardiovascular damage.
A Lindholm, S Henricsson
Verapamil inhibits cyclosporin metabolism.
Lancet. 1987 May 30;1(8544):1262-3.
Abstract/Text
Alain J Romero, Patrick Le Pogamp, Lars-Goran Nilsson, Nolan Wood
Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.
Clin Pharmacol Ther. 2002 Apr;71(4):226-34. doi: 10.1067/mcp.2002.121911.
Abstract/Text
OBJECTIVE: Voriconazole is a broad-spectrum triazole antifungal agent under investigation for opportunistic infections that often target immunosuppressed patients. This study investigated the effect of voriconazole on the pharmacokinetics of cyclosporine (INN, ciclosporin).
METHODS: This was a randomized, double-blind, placebo-controlled, crossover study in kidney transplant recipients with stable renal function who were receiving cyclosporine (150-375 mg/d). During the first study period (7.5 days), subjects in group A received concomitant voriconazole (200 mg every 12 hours); group B received a matched placebo. After a washout period (>or=4 days), subjects were crossed over to the other treatment regimen.
RESULTS: In the 7 subjects who completed both regimens, concomitant administration with voriconazole resulted in a 1.7-fold increase in mean cyclosporine area under the plasma concentration-time curve within a dosage interval (AUC(tau); 90% confidence interval, 1.47 to 1.96). Cyclosporine maximum observed plasma concentration (C(max)) and the time to the first occurrence of C(max) (t(max)) were not affected in a clinically significant manner, but plasma trough concentration (C(min)) was higher in the presence of voriconazole than with placebo. The mean increase in cyclosporine C(min) in subjects who ceased to participate in the study was 2.48-fold (range, 1.88 to 3.03). There were 7 subjects who stopped participating in the study during voriconazole administration. Six of these subjects discontinued the study for reasons that were considered to be drug related, and the majority were attributable to increased cyclosporine levels. Although not serious, all causality-related adverse events were more frequent during voriconazole administration than during placebo administration.
CONCLUSIONS: Mean cyclosporine AUC(tau) increased 1.7-fold in the presence of voriconazole. Therefore, when voriconazole is initiated in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be halved and that blood cyclosporine concentrations be carefully monitored. When voriconazole is discontinued, blood cyclosporine concentrations should be monitored and the cyclosporine dose increased, if necessary.
Francisco M Marty, Colleen M Lowry, Corey S Cutler, Bonnie J Campbell, Karen Fiumara, Lindsey R Baden, Joseph H Antin
Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2006 May;12(5):552-9. doi: 10.1016/j.bbmt.2005.12.032.
Abstract/Text
Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.
M S Shaeffer, D Collier, M F Sorrell
Interaction between FK506 and erythromycin.
Ann Pharmacother. 1994 Feb;28(2):280-1.
Abstract/Text
C Mignat
Clinically significant drug interactions with new immunosuppressive agents.
Drug Saf. 1997 Apr;16(4):267-78.
Abstract/Text
Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).
Shinsuke Kito, Yoshihiko Koga
Visual hallucinations and amnesia associated with zolpidem triggered by fluvoxamine: a possible interaction.
Int Psychogeriatr. 2006 Dec;18(4):749-51. doi: 10.1017/S1041610206214418.
Abstract/Text
S H Preskorn
Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism.
Clin Pharmacokinet. 1997;32 Suppl 1:1-21.
Abstract/Text
This paper presents an overview of the clinically relevant pharmacology of selective serotonin reuptake inhibitors (SSRIs) with an emphasis on their pharmacokinetics and effects on cytochrome P450 (CYP) enzymes. The SSRIs are potent inhibitors of the neuronal reuptake pump for serotonin (5-hydroxytryptamine; 5-HT) and have minimal effects on a number of other sites of actions (e.g. neuroreceptors and fast sodium channels). For this reason, drugs in this class have remarkable similarity as regards acute and maintenance antidepressant efficacy and tolerability profile. However, individual members of this class differ substantially in their pharmacokinetics and effects on CYP enzymes. Most SSRIs have a half-life (t1/2) of approximately 1 day. Fluoxetine, however, has a longer t1/2 of 2 to 4 days, and its active metabolite, norfluoxetine, has an extended t1/2 of 7 to 15 days. Fluoxetine, paroxetine and, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline. There are nonlinear increases in paroxetine plasma concentrations with dosage increases, but proportional changes with citalopram and sertraline. Indirect data suggest that fluoxetine and fluvoxamine also have nonlinear pharmacokinetics over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (approximately 130%) and paroxetine (approximately 50 to 100%) have been observed in healthy elderly (65 to 75 years) persons versus those who are younger. There is an age-gender interaction for sertraline, with its plasma concentrations being 35 to 40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40 to 50% lower in males than in females. Limited data from clinical trials suggest that age-related differences with fluoxetine may be comparable to those of citalopram and paroxetine. Marked differences exist between the SSRIs with regard to effects on specific CYP enzymes and, thus, the likelihood of clinically important pharmacokinetic drug-drug interactions. The most extensive in vitro and in vivo research has been done with fluoxetine, fluvoxamine and sertraline; there has been less with paroxetine and citalopram. The available in vivo data at each drug's usually effective antidepressant dose are summarised below. Citalopram produces mild inhibition of CYP2D6. Fluvoxamine produces inhibition (which would be expected to be clinically meaningful) of two CYP enzymes. CYP1A2 and CYP2C19, and probably a third, CYP3A3/4. Fluoxetine substantially inhibits CYP2D6 and probably CYP2C9/10, moderately inhibits CYP2C19 and mildly inhibits CYP3A3/4. Paroxetine substantially inhibits CYP2D6 but doses not appear to inhibit any other CYP enzyme. Sertraline produces mild inhibition of CYP2D6 but has little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19 or CYP3A3/4. Understanding the similarities and differences in the pharmacology of SSRIs can aid the clinician in optimal use of this important class of antidepressants.
Edoardo Spina, Vincenza Santoro, Concetta D'Arrigo
Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update.
Clin Ther. 2008 Jul;30(7):1206-27.
Abstract/Text
BACKGROUND: The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit > or = 1 CYP isozyme.
OBJECTIVE: The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants.
METHODS: A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peer-reviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications.
RESULTS: Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications.
CONCLUSIONS: Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.
L L Von Moltke, D J Greenblatt, B W Granda, S X Duan, J M Grassi, K Venkatakrishnan, J S Harmatz, R I Shader
Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations.
Br J Clin Pharmacol. 1999 Jul;48(1):89-97.
Abstract/Text
AIMS: To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings.
METHODS: Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes.
RESULTS: The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50 ) of 0.61 microm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by approximately 40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels.
CONCLUSIONS: The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.
L Pichard, G Gillet, C Bonfils, J Domergue, J P Thénot, P Maurel
Oxidative metabolism of zolpidem by human liver cytochrome P450S.
Drug Metab Dispos. 1995 Nov;23(11):1253-62.
Abstract/Text
The aim of this study was to identify the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represents the main way of metabolism in humans. In human liver microsomes, zolpidem was converted to alcohol derivatives. Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities. Liver microsomes from CYP2D6-deficient patients exhibited normal activity. Production of alcohol derivatives was significantly inhibited by anti-CYP3A antibodies and by ketoconazole. Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, CYP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (including propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, aniline, and lauric acid) produced a moderate or no inhibitory effect. cDNA-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in similar amounts. In human hepatocytes in primary culture, zolpidem was extensively and almost exclusively converted to one of the carboxylic acid derivatives, the main species identified in vivo. Treatment of cells with inducers of CYP1A (beta-naphthoflavone) and CYP3A (rifampicin and phenobarbital) greatly increased the rate of production of this metabolite. We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4. Both CYP1A2 and CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor.
Laurian Vlase, Adina Popa, Maria Neag, Dana Muntean, Marcela Achim, Sorin Emilian Leucuţa
Effect of fluvoxamine on the pharmokinetics of zolpidem: a two-treatment period study in healthy volunteers.
Clin Exp Pharmacol Physiol. 2012 Jan;39(1):9-12. doi: 10.1111/j.1440-1681.2011.05625.x.
Abstract/Text
1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed.
© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.
Kristi K Limke, Angela R Shelton, Ellie S Elliott
Fluvoxamine interaction with warfarin.
Ann Pharmacother. 2002 Dec;36(12):1890-2.
Abstract/Text
OBJECTIVE: To report a case of an elevated international normalized ratio (INR) in a patient receiving fluvoxamine and warfarin.
CASE SUMMARY: A 79-year-old white woman was admitted for suicidal thoughts. Her medical history included depression, chronic obstructive pulmonary disorder, asthma, hypertension, atrial fibrillation with pacemaker placement, and breast cancer with lumpectomy and subsequent left mastectomy. Her medication list prior to admission was extensive, including warfarin 5 mg on Sunday, Monday, Wednesday, and Friday; warfarin 2.5 mg on Tuesday, Thursday, and Saturday, and citalopram 10 mg/d. Citalopram was changed to fluvoxamine during her hospital stay. This resulted in an elevated INR that persisted for approximately 7 days.
DISCUSSION: The metabolism of warfarin involves several cytochrome P450 isoenzymes, including CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Fluvoxamine has the potential to inhibit CYP1A2, CYP2C9, CYP2C19, and CYP3A4 to a significant degree. It also has 11 inactive metabolites that may contribute to enzyme inhibition. Fluvoxamine has an extensive elimination half-life of 17-22 hours after a single dose, which increases with multiple dosing by 30-50%. It can take approximately 10 days to reach a steady-state concentration. In the elderly, the half-life is increased by 50%.
CONCLUSIONS: The coadministration of warfarin and fluvoxamine can result in an increase in the anticoagulant effect of warfarin. This anticoagulant effect can be seen for several days after the discontinuation of fluvoxamine. Our case emphasizes the need to closely monitor potential drug interactions in the elderly, especially those concerning fluvoxamine and warfarin.
V Martinelli, A Bocchetta, A M Palmas, M Del Zompo
An interaction between carbamazepine and fluvoxamine.
Br J Clin Pharmacol. 1993 Dec;36(6):615-6.
Abstract/Text
K Mamiya, K Kojima, E Yukawa, S Higuchi, I Ieiri, H Ninomiya, N Tashiro
Phenytoin intoxication induced by fluvoxamine.
Ther Drug Monit. 2001 Feb;23(1):75-7.
Abstract/Text
A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.
Wichai Suntimaleeworakul, Suthiporn Patharachayakul, Sarunyou Chusri
Drug interaction between valproic acid and meropenem: a case report.
J Med Assoc Thai. 2012 Feb;95(2):293-5.
Abstract/Text
Valproic acid and meropenam is commonly co-administrated in neurosurgical patients. Meropenem potentially decreases the valproic acid level, which may cause perioperative seizure. There has been no previous report of drug interaction between valproic acid and meropenem in Thailand. The authors report a patient who faced uncontrolled seizure after co-administrated valproic acid and meropenem. The level of valproic acid was assessed in different times after the administration of meropenem. Rapid decrease of valproic level was detected. However due to the administration of other antiepileptic agents, seizure did not develop. It is important for the physicians to recognize drug interaction between valproic acid and meropenem. Avoiding co-administration of both agents, valproic acid level monitoring and additive of other antiepileptic agents seem to be the appropriate solution.
山村 直敏, 井村薫, 長沼英夫：イヌにおけるvalproic acidとpanipenemの相互作用． 日化療会誌. 46: 6 1998.
Amy M Karch
The grapefruit challenge: the juice inhibits a crucial enzyme, with possibly fatal consequences.
Am J Nurs. 2004 Dec;104(12):33-5.
Abstract/Text
P Pisarik
Blood pressure-lowering effect of adding grapefruit juice to nifedipine and terazosin in a patient with severe renovascular hypertension.
Arch Fam Med. 1996 Jul-Aug;5(7):413-6.
Abstract/Text
Grapefruit juice had been fortuitously noted to elevate the concentration of felodipine in a pharmacological study of the effect of ethanol on felodipine. This effect was later confirmed not only for felodipine but also for three other dihydropyridine calcium channel blockers. I herein present what I believe to be the first case report describing a marked blood pressure-lowering effect of grapefruit juice in a person receiving an antihypertensive regimen of a dihydropyridine calcium channel blocker (nifedipine) and terazosin.
D J Edwards, F H Bellevue, P M Woster
Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice.
Drug Metab Dispos. 1996 Dec;24(12):1287-90.
Abstract/Text
Grapefruit juice inhibits the metabolism of substrates for enzymes of the CYP3A subfamily. However, the identity of the inhibitor has not been established. Grapefruit juice was extracted into methylene chloride and chromatographed by HPLC, and the effect of the HPLC eluent on CYP3A activity was assessed by measuring 6beta-hydroxytestosterone formation in rat liver microsomes. Significant inhibition was associated with a fraction of HPLC eluent containing a single peak, with a retention time of 16 min. The substance producing this peak was isolated using TLC and identified, using NMR and MS, as 6',7'-dihydroxybergamottin (C21H2406; molecular weight, 372), a furanocoumarin (psoralen) compound. The concentration of 6',7'-dihydroxybergamottin required to inhibit 6beta-hydroxytestosterone formation by 50% was 25 microM. Grapefruit juice reduced CYP3A activity to a significantly greater extent (p < 0.05) than did orange juice, which contained no measurable 6',7'-dihydroxybergamottin (28.6% vs. 62.2% of control activity). The addition of 6',7'-dihydroxybergamottin (30 microM) to orange juice decreased CYP3A activity to values comparable to those observed with grapefruit juice. 6',7'-Dihydroxybergamottin is a potent inhibitor of CYP3A activity, accounts for the difference in inhibition between grapefruit juice and orange juice in vitro, and may be primarily responsible for the effects of grapefruit juice on cytochrome P450 activity in humans.
K Fukuda, T Ohta, Y Oshima, N Ohashi, M Yoshikawa, Y Yamazoe
Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction.
Pharmacogenetics. 1997 Oct;7(5):391-6.
Abstract/Text
Four components were isolated from grapefruit juice that inhibit human CYP3A-mediated drug oxidation. The structures of these compounds were identified as furocoumarin derivatives by absorption spectra, APCI-liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance after their purification by reversed-phase high performance liquid chromatography. They include two new furocoumarins, 4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6- (7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimeth yl- 2-octenyl] oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-I- (1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4- hexenyl] oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-4). These furocoumarins are strong candidates for causative agents of grapefruit juice-mediated drug interaction, because of an inhibition potential that is equal to or stronger than the prototypical CYP3A4 inhibitor, ketoconazole, on liver microsomal testosterone 6 beta-hydroxylation.
大森正規, 荒川昌史, 新木信隆, 齋藤鉄男, 杉本孝一, 藤村昭夫：一般内科外来における大衆薬および嗜好品の使用状況調査－Preliminary report－．臨床薬理34: 141S, 2003.
J Lundahl, C G Regårdh, B Edgar, G Johnsson
Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects.
Eur J Clin Pharmacol. 1995;49(1-2):61-7.
Abstract/Text
In this randomised, cross-over study, in nine healthy males given felodipine ER 10 mg PO 200 ml grapefruit juice was found to increase the plasma levels of felodipine even when the juice was taken 24 hours before the drug. Grapefruit juice drunk simultaneously with and 1, 4, 10 or 24 hours before the drug administration resulted in a 32-99% increase in mean Cmax values of felodipine, relative to concomitant water and felodipine intake. The effect on AUC was also significant when juice was taken up to 10 h before the drug. The effect of the interaction decreased with increasing time between juice and drug intake. All treatments produced a significant decrease in diastolic blood pressure and an increase in heart rate in comparison with morning basal values. The change in haemodynamic variables was approximately the same after all treatment combinations. Headache was reported more frequently after treatments including grapefruit juice.
D G Bailey, J Malcolm, O Arnold, J D Spence
Grapefruit juice-drug interactions.
Br J Clin Pharmacol. 1998 Aug;46(2):101-10.
Abstract/Text
The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
M P Ducharme, L H Warbasse, D J Edwards
Disposition of intravenous and oral cyclosporine after administration with grapefruit juice.
Clin Pharmacol Ther. 1995 May;57(5):485-91. doi: 10.1016/0009-9236(95)90032-2.
Abstract/Text
OBJECTIVE: To examine the effect of grapefruit juice on the disposition of cyclosporine after administration of oral and intravenous doses to healthy male subjects.
METHODS: Subjects received two oral doses of cyclosporine (7.5 mg/kg) and two intravenous doses (2.5 mg/kg infused for 3 hours), with each dose separated by a 1-week washout period. Grapefruit juice (250 ml) was ingested immediately before one oral and one intravenous dose and again 2 hours later. Blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine were measured with use of a specific monoclonal radioimmunoassay.
RESULTS: Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versus 1340 ng/ml), as well as area under the curve (6722 versus 10,730 ng . hr/ml) but had no effect on elimination half-life. Absolute bioavailability of cyclosporine was increased from 0.22 to 0.36 (average increase, 62%) by grapefruit juice.
CONCLUSIONS: The lack of effect on systemic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reducing gut wall metabolism. The latter is more likely in view of studies that suggest significant gut wall metabolism of cyclosporine by CYP3A enzymes known to be inhibited by components of grapefruit juice.
J J Lilja, K T Kivistö, J T Backman, P J Neuvonen
Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life.
Eur J Clin Pharmacol. 2000 Aug;56(5):411-5.
Abstract/Text
OBJECTIVE: Grapefruit juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of grapefruit juice dose on the extent of grapefruit juice-triazolam interaction was investigated.
METHODS: In a randomised, four-phase, crossover study, 12 healthy volunteers received 0.25 mg triazolam with water, with 200 ml normal-strength or double-strength grapefruit juice or, on the third day of multiple-dose [three times daily (t.i.d.)] administration of double-strength grapefruit juice. Timed blood samples were collected up to 23 h after dosing, and the effects of triazolam were measured with four psychomotor tests up to 10 h after dosing.
RESULTS: The area under the plasma triazolam concentration time curve (AUC(0-infinity)) was increased by 53% (P < 0.01), 49% (P < 0.01) and 143% (P < 0.001) by a single dose of normal-strength, a single dose of double-strength and multiple-dose administration of double-strength grapefruit juice, respectively. The peak plasma concentration (Cmax) of triazolam was increased by about 40% by a single dose of normal-strength grapefruit juice (P < 0.01) and multiple-dose grapefruit juice (P < 0.01) and by 25% by a single dose of double-strength grapefruit juice (P < 0.05). The elimination half-life (t(1/2)) of triazolam was prolonged by 54% during the multiple-dose grapefruit juice phase (P < 0.001). A significant increase in the pharmacodynamic effects of triazolam was seen during the multiple-dose grapefruit juice phase in the digit symbol substitution test (DSST, P < 0.05), in subjective overall drug effect (P < 0.05) and in subjective drowsiness (P < 0.05).
CONCLUSIONS: Even one glass of grapefruit juice increases plasma triazolam concentrations, but repeated consumption of grapefruit juice produces a significantly greater increase in triazolam concentrations than one glass of juice. The t(1/2) of triazolam is prolonged by repeated consumption of grapefruit juice, probably due to inhibition of hepatic CYP3A4 activity.
Renate Bolley, Carl Zülke, Martin Kammerl, Michael Fischereder, Bernhard K Krämer
Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John's wort.
Transplantation. 2002 Mar 27;73(6):1009.
Abstract/Text
A A Izzo, E Ernst
Interactions between herbal medicines and prescribed drugs: a systematic review.
Drugs. 2001;61(15):2163-75.
Abstract/Text
Despite the widespread use of herbal medicines, documented herb-drug interactions are sparse. We have reviewed the literature to determine the possible interactions between the seven top-selling herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and prescribed drugs. Literature searches were performed using the following databases: Medline (via Pubmed), Cochrane Library, Embase and phytobase (all from their inception to July 2000). All data relating to herb-drug interactions were included regardless of whether they were based on case reports, case series, clinical trials or other types of investigation in humans. In vitro experiments were excluded. Data were extracted by the first author and validated by the second author. 41 case reports or case series and 17 clinical trials were identified. The results indicate that St John's wort (Hypericum perforatum) lowers blood concentrations of cyclosporin, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline; furthermore it causes intermenstrual bleeding, delirium or mild serotonin syndrome, respectively, when used concomitantly with oral contraceptives (ethinylestradiol/desogestrel), loperamide or selective serotonin-reuptake inhibitors (sertaline, paroxetine, nefazodone). Ginkgo (Ginkgo biloba) interactions include bleeding when combined with warfarin, raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone. Ginseng (Panax ginseng) lowers blood concentrations of alcohol and warfarin, and induces mania if used concomitantly with phenelzine. Garlic (Allium sativum) changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin and produces hypoglycaemia when taken with chlorpropamide. Kava (Piper methysticum) increases 'off' periods in Parkinson patients taking levodopa and can cause a semicomatose state when given concomitantly with alprazolam. No interactions were found for echinacea (Echinacea angustifolia, E. purpurea, E. pallida) and saw palmetto (Serenoa repens). In conclusion, interactions between herbal medicines and synthetic drugs exist and can have serious clinical consequences. Healthcare professionals should ask their patients about the use of herbal products and consider the possibility of herb-drug interactions.
J M Wentworth, M Agostini, J Love, J W Schwabe, V K Chatterjee
St John's wort, a herbal antidepressant, activates the steroid X receptor.
J Endocrinol. 2000 Sep;166(3):R11-6.
Abstract/Text
St John's wort (SJW), an extract of the medicinal plant Hypericum perforatum, is widely used as a herbal antidepressant. Recently, this agent has been found to adversely affect the metabolism of various coadministered drugs. Steroid X receptor (SXR), an orphan nuclear receptor, induces hepatic cytochrome P450 gene expression in response to diverse endogenous steroids, xenobiotics and drugs. Here, we report that, when coexpressed with SXR, a reporter construct derived from the cytochrome P450 3A promoter is activated by St John's wort. A GAL4-SXR ligand binding domain (LBD) fusion mediates concentration-dependent transactivation by SJW, whereas a mutant GAL4-SXR fusion, containing substitutions in key residues in a transactivation domain, is inactive. SJW recruits steroid receptor coactivator-1 to SXR in a two-hybrid assay and competes with radiolabelled ligand in binding studies, suggesting it interacts directly with the receptor LBD. Of two constituents of SJW, we find that hyperforin, but not hypericin, mediates both transactivation and coactivator recruitment by SXR. Our observations suggest that SXR activation by St John's wort mediates its adverse interaction with drugs metabolised via the CYP 3A pathway. Future development of SJW derivatives lacking SXR activation, may enable its antidepressant and drug-metabolising properties to be dissociated.
L B Moore, B Goodwin, S A Jones, G B Wisely, C J Serabjit-Singh, T M Willson, J L Collins, S A Kliewer
St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7500-2. doi: 10.1073/pnas.130155097.
Abstract/Text
St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.
Thomas Kupiec, Vishnu Raj
Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.
J Anal Toxicol. 2005 Oct;29(7):755-8.
Abstract/Text
Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.
Bent H Hellum, Zhuohan Hu, Odd Georg Nilsen
Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes.
Basic Clin Pharmacol Toxicol. 2009 Jul;105(1):58-63. doi: 10.1111/j.1742-7843.2009.00412.x. Epub 2009 Apr 3.
Abstract/Text
The aim of this study was to evaluate in vitro the dose-dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S-mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP-modulating herb, showing a dose-dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log-linear dose-dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non-inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug-herb interactions with selected CYP2C19 substrates.
Ophelia Q P Yin, Brian Tomlinson, Mary M Y Waye, Albert H L Chow, Moses S S Chow
Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole.
Pharmacogenetics. 2004 Dec;14(12):841-50.
Abstract/Text
OBJECTIVE: Ginkgo biloba was found to exert a significant inductive effect on CYP2C19 activity. This study was designed to investigate the potential herb-drug interaction between G. biloba and omeprazole, a widely used CYP2C19 substrate, in subjects with different CYP2C19 genotypes.
METHODS: Eighteen healthy Chinese subjects previously genotyped for CYP2C19 were selected. All subjects received a single omeprazole 40 mg at baseline and then at the end of a 12-day treatment period with G. biloba (140 mg, bid). Multiple blood samples were collected over 12 h, and 24 h urine was collected post omeprazole dosing. Plasma and urine concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone, were determined, and their pharmacokinetics calculated non-compartmentally.
RESULTS: Plasma concentrations of omeprazole and omeprazole sulfone were significantly decreased, and 5-hydroxyomeprazole significantly increased following G. biloba administration in comparison to baseline. A significant decrease in the ratio of area under the plasma concentration-time curve (AUC) of omeprazole to 5-hydroxyomeprazole was observed in the homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers, respectively. The decrease was greater in PMs than EMs. No significant changes in the AUC ratios of omeprazole to omeprazole sulfone were observed. Renal clearance of 5-hydroxyomeprazole was significantly decreased after G. biloba, but the change was not significantly different among the three genotype groups.
CONCLUSION: Our results show that G biloba can induce omeprazole hydroxylation in a CYP2C19 genotype-dependent manner and concurrently reduce the renal clearance of 5-hydroxyomeprazole. Co-administration of G. biloba with omeprazole or other CYP2C19 substrates may significantly reduce their effect, but further studies are warranted.
M K Matthews
Association of Ginkgo biloba with intracerebral hemorrhage.
Neurology. 1998 Jun;50(6):1933-4.
Abstract/Text
M Rosenblatt, J Mindel
Spontaneous hyphema associated with ingestion of Ginkgo biloba extract.
N Engl J Med. 1997 Apr 10;336(15):1108. doi: 10.1056/NEJM199704103361518.
Abstract/Text
