title: Pharmacokinetics of phase I nevirapine metabolites following a single dose and at steady state.
abstract: Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (P < 0.01) but decreased for 2-hydroxynevirapine (P < 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (P < 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity.
authors: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, New York, USA.
authors: Patty
authors: P
authors: Fan-Havard
authors: Zhongfa
authors: Z
authors: Liu
authors: Monidarin
authors: M
authors: Chou
authors: Yonghua
authors: Y
authors: Ling
authors: Aurélie
authors: A
authors: Barrail-Tran
authors: David W
authors: DW
authors: Haas
authors: Anne-Marie
authors: AM
authors: Taburet
mesh_terms: D000328:Adult; D001741:Black or African American; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D044466:Asian People; D001711:Biotransformation; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D065702:Cytochrome P-450 CYP2B6; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000208:ethnology / Q000382:microbiology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D019829:Nevirapine / Q000097:blood / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating