Received for publication April 3, 2007.
Revised July 10, 2007.
Accepted for publication July 12, 2007.

Cytochrome P450 Enzymes And Transporters Induced By Anti-HIV Protease Inhibitors In Human Hepatocytes: Implications For Predicting Clinical Drug Interactions

Abstract

Although many of the clinically significant drug interactions of the anti-HIV protease inhibitors (PIs) can be explained by their propensity to inactivate CYP3A enzymes, paradoxically these drugs cause (or lack) interactions with CYP3A substrates that cannot be explained by this mechanism (e.g. alprazolam), To better understand these paradoxical interactions (or lack thereof), we determined the CYPs and transporters induced by varying concentrations (0-25 µM) of two PIs, ritonavir and nelfinavir, and rifampin (positive control), in primary human hepatocytes. At 10 µM, ritonavir and nelfinavir suppressed CYP3A4 activity, but induced its transcripts and protein expression (19- & 12-, and 12- & 6-fold respectively; >2-fold change over control were interpreted as induction). At 10 µM, rifampin induced CYP3A4 transcripts, CYP3A protein and activity by 23-, 12- and 13-fold respectively. Rifampin’s induction of CYP3A activity was significantly correlated with its induction of CYP3A4 transcripts (r=0.96, p<0.05) and CYP3A protein (r=0.89, p<0.05). All three drugs (10 µM) induced CYP2B6 activity by 2-4 fold, 2C8 and 2C9 activity by 2-4 fold and the transcripts of CYP2B6, 2C8 and 2C9 by >3-, 5- and 3-fold respectively. CYP2C19 and 1A2 activity and transcripts were modestly induced (2-fold), whereas, as expected, CYP2D6 was not induced by any of the drugs. Of the transporters studied, protease inhibitors moderately induced MDR1 (ABCB1) and MRP2 (ABCC1) transcripts, but had no or minimal effect on the transcripts of BCRP (ABCG2), OATP1B1 (SLCO1B1) or OATP1B3 (SLCO1B3). Based on these data, we conclude that many of the paradoxical drug interactions (or lack thereof) with the PIs are metabolic- rather than transporter-based and are due to induction of CYP2B6 and 2C enzymes.

Key words: cytochrome P450, hepatocytes, transporters

This article has been cited by other articles:

				M. D Liedtke and R C. Rathbun Warfarin-Antiretroviral Interactions Ann. Pharmacother., February 1, 2009; 43(2): 322 - 328. [Abstract] [Full Text] [PDF]

				M. M Foisy, E. M Yakiwchuk, and C. A Hughes Induction Effects of Ritonavir: Implications for Drug Interactions Ann. Pharmacother., July 1, 2008; 42(7): 1048 - 1059. [Abstract] [Full Text] [PDF]

				A. Gupta, G. M. Mugundu, P. B. Desai, K. E. Thummel, and J. D. Unadkat Intestinal Human Colon Adenocarcinoma Cell Line LS180 Is an Excellent Model to Study Pregnane X Receptor, but Not Constitutive Androstane Receptor, Mediated CYP3A4 and Multidrug Resistance Transporter 1 Induction: Studies with Anti-Human Immunodeficiency Virus Protease Inhibitors Drug Metab. Dispos., June 1, 2008; 36(6): 1172 - 1180. [Abstract] [Full Text] [PDF]

				E. D. Kharasch, D. Mitchell, R. Coles, and R. Blanco Rapid Clinical Induction of Hepatic Cytochrome P4502B6 Activity by Ritonavir Antimicrob. Agents Chemother., May 1, 2008; 52(5): 1663 - 1669. [Abstract] [Full Text] [PDF]