A thorough understanding of the plasma and intracellular levels of antiretroviral drugs and their metabolites is essential in order to judge a compound's actual potential in humans. We have pharmacokinetic data on PMPA and PMEA in plasma and lymphoid cells of macaques. Four macaques were given either PMEA or PMPA (30 mg/kg) as a slow bolus injection and serial measurements of plasma drug concentrations and their mono- and diphosphate derivatives in PBMC, RBC, and lymph nodes were determined over the course of 48 hours. The peak plasma PMEA and PMPA levels in the macaques were 30-52 5M; elimination of PMEA and PMPA from plasma was half-life (t 1/2) of 7.6 hours. The active intracellular metabolites of PMPA and PMEA in macaques reached levels of 0.3-0.5 5M, which persisted in cells for >48 hours. These intracellular metabolites of PMEA and PMPA also showed prolonged half-lives in human PBMC with 5 1/2 of 15 and 49 hours in stimulated and quiescent cells, respectively. The refore, pharmacokinetic data indicate that PMPA has very favorable cellular kinetics that may permit maintenance of effective levels with infrequent ndosing for the treatment and prophylaxis of SIV and HIV infections. FUNDING NIH contract AI65311 and NIH grant RR00166. Fridland, A., Robbins, B., and Tsai, C-C. Cellular pharmacology of the antiretroviral agents PMEA and PMPA in vitro and in vivo. Abstr. 12th World AIDS Conf., 1998.
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