Disposition and Biotransformation of the Antiretroviral Drug Nevirapine in Humans

• Published in: Drug metabolism and disposition Vol. 27; no. 8; pp. 895 - 901
• Main Authors: RISKA, P, LAMSON, M, MACGREGOR, T, SABO, J, HATTOX, S, PAV, J, KEIRNS, J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.08.1999
• Subjects: Adult; AIDS/HIV; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - urine; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biotransformation; Chromatography, High Pressure Liquid; Feces - chemistry; Half-Life; Humans; Hydrolysis; Male; Mass Spectrometry; Medical sciences; Nevirapine - blood; Nevirapine - pharmacokinetics; Nevirapine - urine; Pharmacology. Drug treatments; Spectrophotometry, Ultraviolet; Tissue Distribution; Human; RNA-directed DNA polymerase; Healthy subject; Nevirapine; Enzyme; Transferases; Non nucleoside compound; Oral administration; Retroviridae; Enzyme inhibitor; Metabolism; Lentivirus; Virus; Multiple dose; Nucleotidyltransferases; Antiviral; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X

The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 μCi of [ 14 C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for ∼75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.