ISSX 2013 - HIV Protease Inhibitors

ISSX 2013 - HIV Protease Inhibitors

Published:  29 September 2013

Substrate-Specific Inactivation of CYP3A by the HIV Protease Inhibitors Ritonavir, Saquinavir and Amprenavir

HIV protease inhibitors (PIs), such as ritonavir, saquinavir, and amprenavir, produce profound and clinically significant drug-drug interactions (DDIs) by time-dependent inactivation of CYP3A enzymes. Therefore, it is surprising that these PIs occasionally do not produce a clinically significant DDI with some CYP3A substrates when one is expected. For example, chronic administration of ritonavir significantly increases midazolam AUC but has no effect on alprazolam AUC and this has been shown not to be due to CYP3A4 induction.  Since CYP3A4 has multiple binding sites, we hypothesized that the PIs inactivate CYP3A enzymes in a substrate-dependent manner. Therefore, in the present study, we evaluated the in vitro CYP3A inactivation kinetics of ritonavir, saquinavir or amprenavir with several model CYP3A probe substrates, namely alprazolam, testosterone, nifedipine, alfentanil, or midazolam. Inactivation of CYP3A enzymes in human liver microsomes or rCYP3A4 was quantified by determining the maximum inactivation rate constant (kinact) and the inactivation constant (KI).