This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ?-D-Dioxolane-thymine (D-DOT) is a nucleoside with potent in vitro activity against several nucleoside resistant reverse transcriptase-HIV mutants. Therefore, the single dose intravenous and oral pharmacokinetics of D-DOT were studied in three rhesus monkeys. A 2-compartment open pharmacokinetic model adequately fitted to the plasma and urine data. D-DOT was rapidly and almost completely absorbed (F = 0.82 to 1.06). The average serum beta half-life was 2.11 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 l/kg, respectively, and the average systemic and renal clearances were 0.37 l/kg and 0.16 l/kg. D-DOT reached levels in the CSF in excess of 10 to 20 times the median effective anti-HIV concentration of resistant and wild type mutations. The potent antiretroviral activity of D-DOT against lamivudine and zidovudine resistant HIV-1 mutants, together with an excellent pharmacokinetic profile in rhesus monkeys, suggests that further development is warranted for D-DOT as an anti-HIV drug.
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