今日の臨床サポート

腎障害と薬剤投与量

著者: 浦田元樹 社会医療法人寿楽会 大野記念病院

監修: 浦田元樹 社会医療法人寿楽会 大野記念病院

著者校正/監修レビュー済:2022/03/02
参考ガイドライン:
  1. 日本腎臓学会日本医学放射線学会日本循環器学会:腎障害患者におけるヨード造影剤使用に関するガイドライン2018
  1. 日本腎臓学会:薬剤性腎障害診療ガイドライン2016
患者向け説明資料

概要・推奨   

  1. 機能低下患者では水溶性の未変化体や脂溶性薬物が代謝されて親水性になった代謝物、抱合体が蓄積しやすい。代謝物、抱合体は活性を有する場合に、有害事象などの問題が発生する。
  1. 腎機能の推算法には、血清クレアチニン値を用いたCockcroft-Gaultの式によるクレアチニンクリアランス推算式や日本人向けGFR推算式、シスタチンCを用いた日本人向けGFR推算式などがある。それぞれの推算式の特徴や欠点を理解し、投与設計に用いるのが肝要である。
  1. 患者の腎機能および薬物の尿中未変化体排泄率がわかればGiusti-Hayton法によって投与補正係数を算出し、至適投与量を求めることができる。減量するか投与間隔を延長するかは、薬物の特徴や患者の体格に応じて決定する。
アカウントをお持ちの方はログイン
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
浦田元樹 : 特に申告事項無し[2022年]
監修:浦田元樹 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、主に添付文書などに記載されている腎機能別投与量の参照時の注意点、血液透析における薬物除去率の予測式について加筆を行った。

まとめ

腎機能低下患者での薬物投与量設定とその理由  
機能低下患者での薬物投与設定基本原則
  1. 尿中活性体排泄率の高い薬物(ジゴキシン、ファモチジン、アシクロビル、プレガバリン、バンコマイシンなど)の常用量を腎機能低下患者に投与すると、容易に中毒性副作用が起こる。
  1. 薬物の尿中排泄率が高いほど、また腎機能が低下するほど、1回投与量を減量するか、1回投与量はそのままで投与間隔を延長する必要がある。
  1. ただし、これらの尿中排泄性薬物は、腎機能が低下するほど消失半減期が延長し、血中濃度が定常状態に達する時間も延長するため、感染症などの急性疾患では初回投与量は減量せず、負荷投与することが勧められる。
 
腎排泄型薬物の投与量設定:
(1)腎排泄により消失する薬物――一般的に水溶性薬物は腎排泄型:
  1. 腎臓は異物である水溶性薬物、あるいは肝臓によって極性化(親水性化)反応を受けた薬物の代謝物を尿中に排泄する最も重要な排泄臓器であり、一般的に水溶性薬物は糸球体濾過された後でも尿細管で再吸収されないため、腎排泄型薬物が多い。また脂溶性薬物は一般的に糸球体濾過された後、近位尿細管の刷子縁膜によって速やかに再吸収されるため尿中に排泄されることはなく、再び全身循環に戻る。
  1. 脂溶性薬物は肝臓で主にチトクロームP450(CYP)による第1相反応を受け、水溶性を増した代謝物になる。さらに第2相反応によりグルクロン酸抱合、硫酸抱合などの抱合化反応を受け、非常に極性の高い抱合体となって尿中に排泄されやすくなる。脂溶性薬物は活性を持たない代謝物、抱合体として尿中排泄されるものは多いが、活性体の消失は肝代謝によるため、一般的に腎機能に応じた減量をする必要はない。機能低下患者では水溶性の未変化体や脂溶性薬物が代謝されて親水性になった代謝物、抱合体が蓄積しやすい。ただし活性のない代謝物や抱合体が蓄積しても問題にはならない。
  1. 添付文書に書かれている尿中排泄率は代謝物を含めたものを示すことがあるが、この場合の尿中排泄率は尿中総排泄率を意味するものであり、尿中排泄における未変化体・代謝物の内訳、代謝物の活性の有無および活性代謝物の親化合物に対する活性比が記載されていない場合には腎機能低下患者の投与設計に役に立たない。腎機能低下患者で減量すべきは、尿中活性体排泄率(多くは未変化体排泄率)の高い薬物である。
  1. 薬効によって水溶性や脂溶性という特徴が類似するため、同様の薬物動態を示すことも多く、腎機能が低下していても通常量投与が可能な薬物群と、その薬物群のなかの例外、として整理・記憶することを推奨する。ただし、脂溶性薬物であっても減量する必要のある薬物も例外的に存在するため、次項で解説する。
 
薬物の腎排泄過程

出典

img1:  平田純生先生よりご提供
 
 
 
薬物の消失経路

出典

img1:  平田純生先生よりご提供
 
 
 
腎機能低下にかかわらず通常量投与が可能な薬物とその例外

*有機カオチン輸送系を介して腎排泄される
水色の薬効に入る薬剤はすべて減量の必要がない。

出典

img1:  著者提供
 
 
 
(2)脂溶性薬物でも腎機能低下で減量が必要なものもある:
  1. 前項に示したように一般的に水溶性薬物は腎排泄型であるが、脂溶性薬物がすべて肝代謝型とは限らない。薬物の再吸収と異なり、薬物が尿細管分泌される場合には血管側から尿細管腔側へと濃度勾配に逆らって能動的に輸送される必要がある。そのため尿細管分泌には必ず特殊な輸送系が関与している。尿細管に存在する輸送系(トランスポーター)には有機アニオン輸送系、有機カチオン輸送系およびP糖蛋白質があり、これらは不要な代謝産物や薬物などの生体異物の尿中排泄に重要な役割を果たしている。水溶性薬物は腎臓から排泄されやすいと前述したが、尿細管(特に近位尿細管で)分泌されやすい薬物は必ずしも水溶性の薬物とは限らない。近位尿細管上皮細胞に分布する排泄トランスポーターの基質になる薬物は脂溶性薬物であっても、また蛋白結合率が高い薬物であっても尿中排泄率が高くなることがあるため、要注意である。例えばパーキンソン病や脳卒中後遺症のために用いられるため、血液脳関門を通過しやすく脂溶性が高いアマンタジン(シンメトレル)や、同様にパーキンソン病に用いられるプラミペキソール(ビ・シフロール)の尿中未変化体排泄率が各々90%、72%以上といずれも高いのは、これらの薬物が尿細管分泌を促す有機カチオントランスポーター(OCT1~3)の基質であるためである。
  1. 腎機能低下にかかわらず通常量投与が可能な薬物とその例外:表<図表>
  1. 生体に不必要、あるいは過剰な物質は、近位尿細管の有機アニオン輸送系・カチオン輸送系を介して尿中へ分泌される。有機アニオン輸送系は尿酸や有機カルボン酸など、有機カチオン輸送系はコリンなどの排泄のために用いられる。また、近位尿細管には排泄トランスポーターのP糖蛋白質が発現し、ジゴキシンなどの分泌に関与している。
 
(3)正確な腎機能と尿中活性体排泄率がわかれば腎機能に応じた用量設定が可能:
  1. 腎臓からの排泄率が高い薬物では腎機能低下により排泄が遅延し、正常腎機能者と同じ量・同じ間隔で投与すると、薬物の蓄積により思わぬ副作用を起こすことがある。
  1. ジゴキシンによる食欲不振・視覚異常、イミペネム(チエナム)やファモチジン(ガスター)、アシクロビル(ゾビラックス)による精神錯乱・意識障害、プレガバリン(リリカ)による意識消失、シベンゾリン(シベノール)による低血糖、ベザフィブラート(ベザトールSR)による横紋筋融解症などは、未変化体あるいは活性代謝物の尿中排泄率が高いために活性体が蓄積して発現する、腎機能低下患者に特有な中毒性の副作用といえる。
  1. 腎排泄によって消失する薬物では投与量が同じでも血漿薬物濃度に個人差が生じることがあるが、これは腎機能の個人差によって説明できる。
  1. 例えば加齢によって主に呼吸器機能、心機能とともに、腎血流量が低下し、腎の動脈硬化も進行するため、腎機能は低下し、小柄で虚弱な80歳以上の高齢者では健常青年の1/2程度に腎機能(糸球体濾過値[GFR])が低下するといわれている。GFRを表す優れたマーカーとしてはイヌリンクリアランス(GFR)、実測クレアチニンクリアランス(CCr)があるが、クレアチニンは尿細管分泌されるため、CCrはGFRよりも20~30%程度高めの値になる。
  1. また、たとえGFRやCCrが測定できなくても、筋肉量の少ないフレイル患者を除けば血清クレアチニン値がわかれば推算GFR(eGFR)や推算CCr(eCCr)は予測可能である。
 
腎機能の推算法:
  1. 腎機能の推算には日本腎臓病薬物療法学会web site内のeGFR-CCrの計算が使いやすい。各種の腎機能が推算できるだけでなく体表面積、理想体重も計算可能である。
  1. 計算式:eGFR:推定糸球体ろ過量(日本腎臓学会計算式)

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

D W Cockcroft, M H Gault
Prediction of creatinine clearance from serum creatinine.
Nephron. 1976;16(1):31-41.
Abstract/Text A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.

PMID 1244564
Revised equations for estimated GFR from serum creatinine in Japan.
Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1.
Abstract/Text
PMID 19339088
D Du Bois, E F Du Bois
A formula to estimate the approximate surface area if height and weight be known. 1916.
Nutrition. 1989 Sep-Oct;5(5):303-11; discussion 312-3.
Abstract/Text
PMID 2520314
Emily Hart, Terry E Dunn, Steven Feuerstein, David M Jacobs
Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retrospective Cohort Study.
Pharmacotherapy. 2019 Apr;39(4):443-453. doi: 10.1002/phar.2235. Epub 2019 Mar 21.
Abstract/Text BACKGROUND: Proton pump inhibitors (PPIs) have been linked to acute kidney injury (AKI) and chronic kidney disease (CKD); however, current evidence has only been evaluated in a small number of studies with short follow-up periods. This study examined the association between PPI use and risk of incident AKI and CKD in a large population-based health maintenance organization (HMO) cohort.
METHODS: Patients aged 18 years or older, without evidence of preexisting renal disease, started on PPI therapy, and those continuously enrolled for at least 12 months between July 1993 and September 2008 were identified in an HMO database. Incidences of AKI and CKD were defined using documented International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes or a glomerular filtration rate less than 60 ml/min/1.73 m2 after initiation of PPI therapy. Patients with AKI were followed for up to 90 days (cohort 1), and patients with CKD required at least 1 year of follow-up (cohort 2). Multivariable logistic regression analyses were used to adjust for differences in demographics (excluding race), comorbidities, and medication use between groups.
RESULTS: In 93,335 patients in the AKI cohort, 16,593 of whom were exposed to PPIs, the incidence rate of AKI was higher in the PPI group than nonusers (36.4 vs 3.54 per 1000 person-years, p<0.0001, respectively). In adjusted models, PPI exposure was associated with an increased risk of AKI (adjusted odds ratio [aOR] 4.35, 95% confidence interval [CI] 3.14-6.04, p<0.0001). In 84,600 patients in the CKD cohort, 14,514 of whom were exposed to PPIs, the incidence rate of CKD was higher in the PPI group than nonusers (34.3 vs 8.75 per 1000 person-years, p<0.0001, respectively). In adjusted models, PPIs were associated with a higher risk of CKD compared with controls (aOR 1.20, 95% CI 1.12-1.28, p<0.0001). Associations between PPI use and AKI and CKD persisted in propensity score-matched analyses.
CONCLUSION: The use of PPIs is associated with an increased risk of incident AKI and CKD. This relationship could have a considerable public health impact; therefore, health care provider education and deprescribing initiatives will be necessary to raise awareness and reduce health care burden.

© 2019 Pharmacotherapy Publications, Inc.
PMID 30779194
Y W Lam, S Banerji, C Hatfield, R L Talbert
Principles of drug administration in renal insufficiency.
Clin Pharmacokinet. 1997 Jan;32(1):30-57. doi: 10.2165/00003088-199732010-00002.
Abstract/Text Normal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use. Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLCR) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted. Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent. Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion. Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.

PMID 9012555
J W Cheng, S L Charland, L M Shaw, S Kobrin, S Goldfarb, E J Stanek, S A Spinler
Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay.
Pharmacotherapy. 1997 May-Jun;17(3):584-90.
Abstract/Text STUDY OBJECTIVE: To determine digoxin pharmacokinetics in subjects with different degrees of renal function using fluorescence polarization immunoassay (FPIA), which is associated with less interference from digoxin-like immunoreactive substances (DLIS) than radioimmunoassay.
SETTING: University hospital clinical research center.
PARTICIPANTS: Eighteen subjects (mean age 44 yrs) with different degrees of renal function: group 1, creatinine clearance (Clcr) below 10 ml/minute; group 2, Clcr 10-50 ml/minute; and group 3, Clcr greater than 50 ml/minute (6 patients in each group).
INTERVENTION: Over 5-7 days, 15 serum samples were collected after a single intravenous dose of digoxin 7 or 10 micrograms/kg actual body weight (WT) for serum concentration measurements by FPIA. Two-compartment pharmacokinetic parameters (zero-time intercept of the concentration-time curve of the initial distribution phase [A], zero-time intercept of the concentration-time curve of the terminal elimination phase [B], initial distribution phase constant [alpha], terminal elimination rate constant [beta], volume of distribution in the central compartment [Vc] and at steady state [Vss], total body clearance [Cl], mean residence time [MRT], area under the concentration-time curve [AUC]) were determined using a nonlinear least squares regression program.
MEASUREMENTS AND MAIN RESULTS: No significant differences were found among groups for A, B, alpha, beta, beta-half-life Vc/WT, MRT, AUC, and Cl/WT. Significant differences were observed in Vss/WT (4.8 +/- 1.0, 6.6 +/- 0.5, 6.4 +/- 0.7 L/kg) between group 1 versus group 2 and group 1 versus group 3 (p < 0.01). Measured Clcr was correlated with Cl (r2 = 0.40, p < 0.01), Cl/WT (r2 = 0.29, p < 0.05), Vss (r2 = 0.35, p = 0.01), and Vss/WT (r2 = 0.24, p < 0.05).
CONCLUSION: This study confirmed that Vss is smaller in patients with chronic renal failure (Clcr < 10 ml/min) than those without chronic renal failure. Therefore, previous recommendations that lower digoxin loading doses should be administered in patients with renal failure are applicable to digoxin serum concentration monitoring using FPIA.

PMID 9165563
R W Jelliffe
An improved method of digoxin therapy.
Ann Intern Med. 1968 Oct;69(4):703-17. doi: 10.7326/0003-4819-69-4-703.
Abstract/Text
PMID 5682245
W J Jusko, M Weintraub
Myocardial distribution of digoxin and renal function.
Clin Pharmacol Ther. 1974 Sep;16(3):449-54. doi: 10.1002/cpt1974163part1449.
Abstract/Text
PMID 4414761
M M Reidenberg, M Affrime
Influence of disease on binding of drugs to plasma proteins.
Ann N Y Acad Sci. 1973 Nov 26;226:115-26. doi: 10.1111/j.1749-6632.1973.tb20474.x.
Abstract/Text
PMID 4520390
Abstract/Text A rapid ultrafiltration technique was used to measure the free (unbound) fraction of disopyramide in serum obtained from 14 normal volunteers, 6 chronic hemodialysis patients, and 10 renal transplant recipients. The disopyramide-free fraction varied more than tenfold at a corresponding total (free plus bound) serum disopyramide concentration of 3 micrograms/ml and was related to the concentration of an acute-phase protein, alpha-1-acid glycoprotein (AAG), in patient serum. Moreover, disopyramide-free fraction values were nearly twofold lower than normal in serum specimens obtained from those renal patients and transplant recipients with corresponding AAG serum concentrations greater than 100 mg/100 ml. AAG concentrations varied tenfold in patient serum and were on average nearly three times higher than AAG concentrations in normal volunteer serum. These findings suggested that the free fraction of disopyramide and possibly other drugs which bind extensively to AAG may be lower, and the interpatient variability in drug binding may be much more pronounced in serum obtained from hemodialysis patients and transplant recipients than previously recognized.

PMID 3881959
T Arima, Y Motoyama, K Nagata, T Kondo
Serum glycoproteins in the liver diseases. II. Radioimmunoassay of alpha-1 acid glycoprotein.
Gastroenterol Jpn. 1976;11(4):307-12.
Abstract/Text A radioimmunoassay for human alpha1-acid glycoprotein has been developed. 97.8% of 125I-alpha1-acid glycoprotein prepared for the assay were immunoprecipitable with specific anti-sera against the protein. alpha1-acid glycoprotein concentration in sera from normal adults was found to range between 70 and 114 mg/100 ml, with a mean of 93. Fulminant hepatitis, liver cirrhosis or chronic active hepatitis with sublobular necrosis caused a significant lowering of alpha1-acid glycoprotein concentration. Sera obtained from patients with acute hepatitis in convalescence, chronic inactive hepatitis or primary biliary cirrhosis gave normal concentration of the glycoprotein.

PMID 1017593
A O Iyun, G T Tucker
Antipyrine kinetics in Nigerian women in chronic renal failure.
Afr J Med Med Sci. 1982 Mar;11(1):7-9.
Abstract/Text Antipyrine was given orally to five patients with Chronic renal failure and nine normal subjects. Plasma antipyrine levels were measured by high pressure liquid chromatography method, the plasma half-life of the drug was determined and used as an index of drug oxidation. The mean (+/- s.d.) plasma antipyrine half-life in patients with chronic renal failure (7.8 +/- 2.6 h) was significantly shorter than in normal subjects (13.1 +/- 2.3 h) (P less than 0.001). There was no significant difference in the volume of distribution but there was a significant difference in the clearance in ml.kg-1h-1 (P less than 0.001). The results suggest that oxidation of antipyrine by hepatic microsomal enzymes is increased in patients with chronic renal failure. The role of this in the apparent resistance among our patients to antihypertensive agents needs further study.

PMID 6291357
N Weyer, T Kröplin, L Fricke, H Iven
Human thiopurine S-methyltransferase activity in uremia and after renal transplantation.
Eur J Clin Pharmacol. 2001 May;57(2):129-36. doi: 10.1007/s002280100287.
Abstract/Text UNLABELLED: In addition to cyclosporin and steroids, azathioprine is frequently used for immunosuppression after renal transplantation. Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. A genetic polymorphism was shown with 1 in 300 homozygous for a TPMT deficiency. These subjects carry the risk of severe myelosuppression when treated with azathioprine.
OBJECTIVE: To investigate the influence of hemodialysis on TPMP activity in uremic patients and the effect of azathioprine treatment on enzyme activity.
METHODS: The assay for measurement of TPMT activity in packed red blood cells is based on a non-radioactive conversion of 6-thioguanine to 6-methylthioguanine. In 251 patients, TPMT activity was determined before and after a 4-h period of hemodialysis. In 49 patients (26 on azathioprine, 23 on mycophenolate mofetil as control group), TPMT activity was regularly determined during the first 120 days after renal transplantation.
RESULTS: TPMT activity is elevated in red blood cells of uremic patients before hemodialysis when compared with TPMT activity after hemodialysis. The latter is comparable to the activity in healthy subjects. In patients treated with azathioprine, the TPMT activity showed a slow increase that declined to pre-treatment values when azathioprine was withdrawn. This could not be observed in patients treated with mycophenolate mofetil.
CONCLUSIONS: In uremic patients, TPMT activity is activated by some uremic factors that are removed by hemodialysis. In contrast to what has been observed before, dialysis shifted the TPMT activity close to that of a healthy control group. In patients treated with azathioprine after renal transplantation, the observed increase of TPMT activity could possibly be the result of enzyme induction.

PMID 11417444
Thomas D Nolin, Kofi Appiah, Scott A Kendrick, Phuong Le, Ellen McMonagle, Jonathan Himmelfarb
Hemodialysis acutely improves hepatic CYP3A4 metabolic activity.
J Am Soc Nephrol. 2006 Sep;17(9):2363-7. doi: 10.1681/ASN.2006060610. Epub 2006 Aug 9.
Abstract/Text The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.

PMID 16899515
T P Gibson
Renal disease and drug metabolism: an overview.
Am J Kidney Dis. 1986 Jul;8(1):7-17. doi: 10.1016/s0272-6386(86)80148-2.
Abstract/Text Renal disease will perturb the disposition of drugs that primarily depend upon renal excretory function for elimination. While changes in drug half-life (T1/2) are often cited as evidence of altered drug disposition, it must be remembered that T1/2 is a dependent variable whose magnitude varies directly with volume of distribution (Vd) and indirectly with total body clearance (ClT). ClT is the one term that succinctly describes drug elimination. ClT is defined as the sum of the renal (ClR) and nonrenal (ClNR), or metabolic, clearances of a drug. Renal failure has been shown to alter the hepatic microsomal mixed-function oxidase system of drug metabolizing enzymes. Therefore, in end-stage renal failure, the potential exists for the modification of the disposition of drugs whose elimination is primarily hepatic. The kidneys themselves contain many of the enzymes important in hepatic drug metabolism. Drugs such as morphine, paracetamol, and p-aminobenzoic acid are metabolized in the kidney and experimental renal disease has been shown to reduce drug metabolism in the diseased kidney compared with the contralateral normal kidney. Renal disease, then, has the potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidneys. It can no longer be assumed that the pharmacokinetics of drugs that are disposed mainly by metabolism will be unaltered in renal failure.

PMID 3524205
T P Gibson, A J Atkinson, E Matusik, L D Nelson, W A Briggs
Kinetics of procainamide and N-acetylprocainamide in renal failure.
Kidney Int. 1977 Dec;12(6):422-9. doi: 10.1038/ki.1977.133.
Abstract/Text Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.

PMID 609192
Judith Naud, Josée Michaud, Caroline Boisvert, Karine Desbiens, Francois A Leblond, Andrew Mitchell, Christine Jones, Alain Bonnardeaux, Vincent Pichette
Down-regulation of intestinal drug transporters in chronic renal failure in rats.
J Pharmacol Exp Ther. 2007 Mar;320(3):978-85. doi: 10.1124/jpet.106.112631. Epub 2006 Nov 29.
Abstract/Text Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.

PMID 17135344
S-M Huang, R Temple, S Xiao, L Zhang, L J Lesko
When to conduct a renal impairment study during drug development: US Food and Drug Administration perspective.
Clin Pharmacol Ther. 2009 Nov;86(5):475-9. doi: 10.1038/clpt.2009.190.
Abstract/Text To optimize drug therapy for individuals, it is critical to understand how various intrinsic (e.g., age, gender, race, genetics, organ impairment) and extrinsic factors (e.g., diet, smoking, concomitantly administered drugs) affect drug exposure and response.(1) Up to now, it has been far easier to discover effects on exposure caused by these factors, and the US Food and Drug Administration (FDA) has published several guidance documents with recommendations on how to evaluate these factors during drug development.

PMID 19844224
L Dettli
Drug dosage in renal disease.
Clin Pharmacokinet. 1976;1(2):126-34. doi: 10.2165/00003088-197601020-00004.
Abstract/Text Based on the well known linear relationship between the overall drug elimination rate constant and the endogenous creatinine clearance, it is shown how individual drug elimination parameters in patients with renal disease can be estimated from the patient's creatinine clearance or serum creatinine concentration. By means of a simple nomogram the elimination rate fraction is determined which describes the elimination rate of the drug as a fraction of its normal elimination rate constant. Based on the estimated elimination rate fraction the dosage regimen in the patient with renal disease is individually modified according to pharmacokinetic principles. At present the described method can be used with 45 different drugs.

PMID 797495
Motoki Urata, Yuki Narita, Masaki Fukunaga, Daisuke Kadowaki, Sumio Hirata
Simple Formula for Predicting Drug Removal Rates During Hemodialysis.
Ther Apher Dial. 2018 Oct;22(5):485-493. doi: 10.1111/1744-9987.12675. Epub 2018 Jul 10.
Abstract/Text The present study sought to derive a simple formula for predicting the drug removal rates during hemodialysis. We examined the relationship between drug removal rates during hemodialysis and the molecular weights or pharmacokinetic parameters of injectable drugs (N = 90) obtained from pharmaceutical interview forms in Japan. Stepwise multiple regression analysis with the removal rate by hemodialysis as the objective variable adjusted for molecular weight or pharmacokinetic parameters as explanatory variables, showed that the logarithm of molecular weight (B = -18.87), the protein binding rate (B = -0.40), and the fraction of the unchanged drug excreted into the urine/volume of distribution (B = 0.05) were significantly and independently associated with drug removal rate by hemodialysis (α = 90.78, adjusted R2  = 0.64, P = 2.2e-16 ). Our data demonstrated that molecular weight, protein binding rate, and volume of distribution were important factors affecting drug removal during hemodialysis, and that our simple regression equation could be used to predict the drug removal rate during hemodialysis.

© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.
PMID 29987905
Marina Murakami, Yuki Narita, Motoki Urata, Misato Ichigi, Sakura Nakatani, Yuki Kondo, Yoichi Ishitsuka, Tetsumi Irie, Sumio Hirata
Improved Formula for Predicting Hemodialyzability of Intravenous and Oral Drugs.
Blood Purif. 2021;50(6):865-875. doi: 10.1159/000513152. Epub 2021 Mar 9.
Abstract/Text BACKGROUND: The rate of drug removal by hemodialysis needs to be considered when designing drug dosage regimens for patients on hemodialysis. We previously developed a simplified equation to predict the removal rates of intravenously administered drugs by hemodialysis. Here, we addressed shortcomings of this equation and developed a more accurate equation that can also predict the removal rates of orally administered drugs.
METHODS: A total of 70 drugs with known pharmacokinetic and physical parameters and drug removal rates that were measured during hemodialysis in clinical cases were randomly assigned at a 4:1 ratio to a training data group or a test data group. A prediction equation was developed by performing stepwise multiple regression analyses using the training data (i.e., the removal rate by hemodialysis) as the objective variable and pharmacokinetic parameters as the explanatory variables. The equation was validated using the test data.
RESULTS: Multiple regression analyses revealed that molecular weight (MW), protein binding rate, and fraction excreted unchanged in urine relative to the volume of distribution (Vd) were independently correlated with the drug clearance rate (adjusted coefficient of determination, 0.83; p = 2.2e-16). The following equation was obtained: drug removal rate by hemodialysis (%) = -17.32 × [log (MW)] - 0.39 × [protein binding rate (%)] + 0.06 × [fraction excreted unchanged in urine (%)/Vd (L/kg)] + 83.34. Validation of the equation using the test data showed a very high correlation between predicted and measured reduction rate (R = 0.93, p = 1.87e-6). Mean error was -3.34 (95% confidence interval: -10.03, 3.35), mean absolute error was 9.59, and root mean square error was 16.48.
CONCLUSION: The modified equation derived in this study using pharmacokinetic and physical parameters as variables precisely predicted the removal rates of both intravenous and oral drugs by hemodialysis.

© 2021 S. Karger AG, Basel.
PMID 33690227
Tobias Dreischulte, Daniel R Morales, Samira Bell, Bruce Guthrie
Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury.
Kidney Int. 2015 Aug;88(2):396-403. doi: 10.1038/ki.2015.101. Epub 2015 Apr 15.
Abstract/Text Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.

PMID 25874600

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから