Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis

Journal Article · Tue Jan 15 04:00:00 EST 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.09.007· OSTI ID:21077901

Divi, Rao L ^[1]; Doerge, Daniel R; Twaddle, Nathan C ^[2]; Shockley, Marie E ^[1]; St Claire, Marisa C; Harbaugh, Jeffrey W; Harbaugh, Steven W ^[3]

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1. Carcinogen-DNA Interactions Section, LCBG, CCR, National Cancer Institute, Bldg. 37. Rm. 4032 NIH, 37 Convent Drive, Bethesda, MD 20892-4255 (United States)
2. Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, HFT 110, 3900 NCTR Road, Jefferson, AR 72079 (United States)
3. BioQual Inc., 2501 Research Blvd., Rockville, MD 20850 (United States)

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 (registered) . The patas (n = 3) AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations (C{sub max}) for AZT and 3TC were 2.35 and 2.65 {mu}g/ml, respectively, and were observed at 0.83 h (T{sub max}). C{sub max} was 13.34 {mu}g/ml for the AZT-glucuronide (AZT-G) and was 0.023 {mu}g/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{sup -1}, were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h{sup -1}) resulting in AUC{sub (0-{infinity})} values of 6.97 {mu}g/ml h for 3TC, 2.99 {mu}g/ml h for AZT, 20.5 {mu}g/ml h for AZT-G and 0.002 for AMT 6.97 {mu}g/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.

• OSTI ID: 21077901
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 226; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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