title: Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450.
abstract: 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 (K(i) = 270 microM). 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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. derickso@rdg.boehringer-ingelheim.com
authors.forename: D A
authors.initials: DA
authors.lastname: Erickson
authors.forename: G
authors.initials: G
authors.lastname: Mather
authors.forename: W F
authors.initials: WF
authors.lastname: Trager
authors.forename: R H
authors.initials: RH
authors.lastname: Levy
authors.forename: J J
authors.initials: JJ
authors.lastname: Keirns
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004347:Drug Interactions; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D019829:Nevirapine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019829:Nevirapine; D014217:Troleandomycin; D054303:HIV Reverse Transcriptase; D007654:Ketoconazole