Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients

被引：71

作者：

Wyen, C. ^{[2
]}

Fuhr, U. ^{[1
]}

Frank, D.

Aarnoutse, R. E. ^{[3
]}

Klaassen, T. ^{[1
]}

Lazar, A. ^{[1
]}

Seeringer, A. ^{[4
]}

Doroshyenko, O. ^{[1
]}

Kirchheiner, J. C. ^{[4
]}

Abdulrazik, F. ^{[2
]}

Schmeisser, N. ^{[2
]}

Lehmann, C. ^{[2
]}

Hein, W. ^{[5
]}

Schoemig, E. ^{[1
]}

Burger, D. M. ^{[3
]}

Faetkenheuer, G. ^{[2
]}

Jetter, A. ^{[1
,6
]}

机构：

[1] Univ Cologne, Dept Pharmacol, Cologne, Germany

[2] Hosp Univ Cologne, Dept Internal Med, Cologne, Germany

[3] Radboud Univ Nijmegen Med Ctr, Dept Clin Pharm, Nijmegen, Netherlands

[4] Univ Ulm, Dept Pharmacol Nat Prod & Clin Pharmacol, D-89069 Ulm, Germany

[5] Hosp Univ Cologne, Dept Clin Chem, Cologne, Germany

[6] Univ Zurich Hosp, Dept Internal Med, Div Clin Pharmacol & Toxicol, CH-8091 Zurich, Switzerland

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2008年 / 84卷 / 01期

关键词：

D O I：

10.1038/sj.clpt.6100452

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

This study aimed to quantify the inhibition of cytochrome p450 (CYP3A), CYP2D6, and p-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. activities, demographics, and genetic polymorphisms in CYP3a, CYP2D6, and P-glycoprotein were tested as covariates. oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. in CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. in conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.

引用

页码：75 / 82

页数：8

共 49 条

[1] Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers [J].