title: Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis.
abstract: Because of their similarity to humans, non-human primates constitute useful preclinical models in which to examine potential human drug toxicities. Antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) toxicity is currently under investigation in Erythrocebus patas monkeys, and whereas NRTI pharmacokinetics have been studied in other monkey species, pharmacokinetics for Zidovudine plus Lamivudine (AZT/3TC) dosing have not been reported in the patas. Here we present 24 h serum pharmacokinetic parameters after a single oral exposure to the combination of AZT (40 mg) and 3TC (24 mg), doses equivalent to a human daily dose of Combivir. The patas (n=3) AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations (Cmax) for AZT and 3TC were 2.35 and 2.65 microg/ml, respectively, and were observed at 0.83 h (Tmax). Cmax was 13.34 microg/ml for the AZT-glucuronide (AZT-G) and was 0.023 microg/ml for the potentially toxic minor metabolite 3'-amino-3'-deoxythymidine (AMT), both occurring at about 1 h after dosing. Similar elimination half-times, 0.70 and 0.68 h(-1), were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h(-1)) resulting in AUC(0-infinity) values of 6.97 microg/ml h for 3TC, 2.99 microg/ml h for AZT, 20.5 microg/ml h for AZT-G and 0.002 for AMT 6.97 microg/ml h. This study shows similar metabolism and pharmacokinetics for oral administration of AZT/3TC in the adult patas monkey, other primate species and humans. The data validate the use of the patas monkey for studies of NRTI toxicity.
authors.affiliation: Carcinogen-DNA Interactions Section, LCBG, CCR, National Cancer Institute, Bldg. 37. Rm. 4032 NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
authors.forename: Rao L
authors.initials: RL
authors.lastname: Divi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Twaddle
authors.forename: Marie E
authors.initials: ME
authors.lastname: Shockley
authors.forename: Marisa C
authors.initials: MC
authors.lastname: St Claire
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Harbaugh
authors.forename: Steven W
authors.initials: SW
authors.lastname: Harbaugh
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Poirier
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004338:Drug Combinations; D004901:Erythrocebus patas; D006207:Half-Life; D019259:Lamivudine / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D015215:Zidovudine / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine