Vol. 30, Issue 12, 1523-1531, December 2002

Metabolism of Stavudine-5'-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats

Chun-Lin Chen, Gengli Yu, T. K. Venkatachalam, and Fatih M. Uckun

Drug Discovery Program (C.-L.C., F.M.U.), Departments of Pharmaceutical Sciences (C.-L.C., F.M.U.), Chemistry (G.Y., T.K.V.), and Immunology (F.M.U.), Parker Hughes Institute, St. Paul, Minnesota

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 of p-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), and p-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.