Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450

Nevirapine (NVP), a non-nucleoside inhibitor of HIV-1 reverse transcriptase , is concomitantly administered to patients with a variety of medications. To assess the potential for its involvement in drug interactions, cytochrom e P-450 (CYP) reaction phenotyping of NVP to its four oxidative metabolites , 2-, 3-, 8-, and 12-hydroxyNVP, was performed. The NVP metabolite formatio n rates by characterized human hepatic microsomes were best correlated with probe activities for either CYP3A4 (2- and 12-hydroxyNVP) or CYP2B6 (3- an d 8-hydroxyNVP). In studies with cDNA-expressed human hepatic CYPs, 2- and 3-hydroxyNVP were exclusively formed by CYP3A and CYP2B6, respectively. Mul tiple cDNA-expressed CYPs produced 8- and 12-hydroxyNVP, although they were produced predominantly by CYP2D6 and CYP3A4, respectively. Antibody to CYP 3A4 inhibited the rates of 2-, 8-, and 12-hydroxyNVP formation by human hep atic microsomes, whereas antibody to CYP2B6 inhibited the formation of 3- a nd 8-hydroxyNVP. Studies using the CYP3A4 inhibitors ketoconazole, troleand omycin, and erythromycin suggested a role for CYP3A4 in the formation of 2- , 8-, and 12-hydroxyNVP. These inhibitors were less effective or ineffectiv e against the biotransformation of NVP to 3-hydroxyNVP. Quinidine very weak ly inhibited only 8-hydroxyNVP formation. NVP itself was an inhibitor of on ly CYP3A4 at concentrations that were well above those of therapeutic relev ance (K-i = 270 mu M). Collectively, these data indicate that NVP is princi pally metabolized by CYP3A4 and CYP2B6 and that it has little potential to be involved in inhibitory drug interactions.