Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors

The capacity of three clinically available nonnucleoside reverse transcript ase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 ( CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevir apine, and efavirenz produced negligible inhibition of phenacetin O-deethyl ation (CYP1A2) or dextromethorphan O-demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C1 9), but these CYP isoforms were importantly inhibited by delavirdine and ef avirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upo n initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP-mediated drug biotransformation. However, the model does not in corpora te interactions attributable to enzyme induction. Journal of Clinical Pharm acology, 2001;41:85-91 (C) 2001 the American College of Clinical Pharmacolo gy.