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Received for publication August 11, 2004.
Revised September 30, 2004.
Accepted for publication October 26, 2004.
HIV protease inhibitors (PI's) are inhibitors of CYP3A enzymes but the mechanism is poorly defined. In this study, time- and concentration-dependent decreases in activity as defined by kinact (maximum rate of inactivation) and KI (inhibitor concentration that gives 50% maximal inactivation) of CYP3A by amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir were quantified using testosterone 6
-hydroxylation as a marker for CYP3A activity with recombinant CYP3A4(+b5), recombinant CYP3A5, and pooled human liver microsomes (HLM's). All the PI's, except indinavir, displayed inactivation with CYP3A4(+b5) and HLM's. Ritonavir was the most potent (KI = 0.10 and 0.17 µM)and demonstrated high kinact values (0.32 and 0.40 min-1) with both CYP3A4(+b5) and HLM's. Ritonavir was not significantly depleted by high-affinity binding with CYP3A4(+b5) and confirmed that estimation of reversible inhibition was confounded with irreversible inhibition. For CYP3A5, nelfinavir exhibited the highest kinact (0.47 min-1) but ritonavir was the most potent (KI = 0.12 µM). Saquinavir and indinavir did not show time- and concentration-dependent decreases in activity with CYP3A5. Spectrophototmetrically determined metabolic intermediate complex formation was observed for all of the PI's with CYP3A4(+b5), except for lopinavir and saquinavir. The addition of nucleophilic and free aldehyde trapping agents, free iron and reactive oxygen species scavengers did not prevent inactivation of CYP3A4(+b5) by ritonavir, amprenavir or nelfinavir, but glutathione decreased the inactivation by saquinavir (17%) and catalase decreased the inactivation by lopinavir (39%). In conclusion, all the PI's exhibited mechanism-based inactivation and predictions of the extent and time-course of drug interactions with PI's could be underestimated if based solely on reversible inhibition.
Key words:
CYP3A, HIV protease inhibitors, cytochrome P450, drug inhibition, drug interactions, mechanism-based inactivation
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