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

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Wyen C, Fuhr U, Frank D, Aarnoutse RE, Klaassen T, Lazar A, Seeringer A, Doroshyenko O, Kirchheiner JC, Abdulrazik F, Schmeisser N, Lehmann C, Hein W, Schomig E, Burger DM, Fatkenheuer G, Jetter A

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

Clin Pharmacol Ther. 2008 Jul;84(1):75-82. doi: 10.1038/sj.clpt.6100452. Epub 2008 Jan 9.

PubMed ID

18183034 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ritonavir	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details