Abstract
We examined the pharmacokinetics and metabolism of the experimental nucleoside reverse transcriptase inhibitor compound stampidine in mice, dogs, and cats. Also reported is the identification ofp-bromophenyl sulfate (p-Br-Ph-S) as a major in vivo phase II metabolite of stampidine. Liver cytosol was shown to take part in the hydrolysis of stampidine to form alaninyl-STV-monophosphate (Ala-STV-MP), 2′,3′-didehydro-3′-deoxythymidine (STV), andp-bromophenol; p-bromophenol was further sulfonated by sulfotransferase to form p-Br-Ph-S. Notably, plasma concentrations of stampidine >4 logs higher than its IC50 value can be achieved in both dogs and cats after its p.o administration at a 100-mg/kg dose level. In dogs as well as cats, stampidine was metabolized to yield micromolar concentrations of the active metabolites ala-STV-MP and STV, which is similar to the metabolism of stampidine in mice. These findings encourage the further development of this new antiviral agent for possible clinical use in human immunodeficiency virus-infected patients.
Footnotes
- Abbreviations used are::
- HIV
- human immunodeficiency virus
- NRTI
- nucleoside reverse transcriptase inhibitor
- Ala-STV-MP
- alaninyl-STV-monophosphate
- STV
- 2′,3′-didehydro-3′-deoxythymidine
- HPLC
- high-performance liquid chromatography
- PAPS
- adenosine 3′-phosphate 5′-phosphosulfate
- P450
- cytochrome P450
- p-Br-Ph-S
- p-bromophenyl sulfate
- TLC
- thin layer chromatography
- AUC
- are under the concentration-time curve
- PLE
- porcine liver esterase
- MS
- mass spectrometry
- RT
- retention time
- Received July 8, 2002.
- Accepted September 16, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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