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阿托伐他汀联合用药可能通过抑制肠道P-糖蛋白介导的分泌来增加地高辛的浓度。

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

作者信息

Boyd R A, Stern R H, Stewart B H, Wu X, Reyner E L, Zegarac E A, Randinitis E J, Whitfield L

机构信息

Department of Pharmacokinetics, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.

出版信息

J Clin Pharmacol. 2000 Jan;40(1):91-8. doi: 10.1177/00912700022008612.

Abstract

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

摘要

在两项研究中,对24名健康志愿者评估了阿托伐他汀对地高辛药代动力学的影响。受试者每天服用0.25mg地高辛,共20天,前10天单独给药,后10天与10mg或80mg阿托伐他汀同时给药。服用10mg阿托伐他汀后,平均稳态血浆地高辛浓度未发生变化。地高辛与80mg阿托伐他汀同时给药后的平均稳态血浆地高辛浓度略高于单独服用地高辛后的浓度,导致Cmax和AUC(0 - 24)值分别升高20%和15%。由于tmax和肾清除率未受到显著影响,结果表明在阿托伐他汀存在的情况下,地高辛的吸收程度增加。已知地高辛会经历由P - 糖蛋白介导的肠道分泌。由于阿托伐他汀是CYP3A4底物,许多CYP3A4底物也是P - 糖蛋白转运的底物,因此研究了阿托伐他汀及其代谢产物对人结肠癌细胞系(Caco - 2)单层中P - 糖蛋白介导的地高辛转运的影响。在该模型系统中,阿托伐他汀表现出流出或分泌动力学,K(m)为110μM。阿托伐他汀(100μM)抑制地高辛分泌(从单层的基底外侧向顶端转运)58%,这与已知的P - 糖蛋白转运抑制剂维拉帕米所观察到的抑制程度相当。因此,80mg阿托伐他汀共同给药导致的稳态地高辛浓度升高可能是由于抑制了地高辛向肠腔的分泌。

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