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Vol. 27, Issue 12, 1488-1495, December 1999
Department of Drug Metabolism and Pharmacokinetics (D.A.E.,
J.J.K.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,
Connecticut; and Department of Pharmaceutics and Medicinal Chemistry
(G.M., W.F.T., R.H.L.), University of Washington, Seattle, Washington
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, cytochrome P-450 (CYP) reaction phenotyping of NVP to its
four oxidative metabolites, 2-, 3-, 8-, and 12-hydroxyNVP, was
performed. The NVP metabolite formation rates by characterized human
hepatic microsomes were best correlated with probe activities for
either CYP3A4 (2- and 12-hydroxyNVP) or CYP2B6 (3-and 8-hydroxyNVP). In
studies with cDNA-expressed human hepatic CYPs, 2- and 3-hydroxyNVP were exclusively formed by CYP3A and CYP2B6, respectively. Multiple cDNA-expressed CYPs produced 8- and 12-hydroxyNVP, although they were
produced predominantly by CYP2D6 and CYP3A4, respectively. Antibody to
CYP3A4 inhibited the rates of 2-, 8-, and 12-hydroxyNVP formation by
human hepatic microsomes, whereas antibody to CYP2B6 inhibited the
formation of 3- and 8-hydroxyNVP. Studies using the CYP3A4 inhibitors
ketoconazole, troleandomycin, and erythromycin suggested a role for
CYP3A4 in the formation of 2-, 8-, and 12-hydroxyNVP. These inhibitors
were less effective or ineffective against the biotransformation of NVP
to 3-hydroxyNVP. Quinidine very weakly inhibited only 8-hydroxyNVP
formation. NVP itself was an inhibitor of only CYP3A4 at concentrations
that were well above those of therapeutic relevance
(Ki = 270 µM). Collectively, these
data indicate that NVP is principally metabolized by CYP3A4 and CYP2B6 and that it has little potential to be involved in inhibitory drug interactions.
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