2-aminopurine-dioxolane and dioxolane-thymine

Beta-D-dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h(-1); fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

Topics: Administration, Oral; Animals; Antiviral Agents; Area Under Curve; Calibration; Chromatography, High Pressure Liquid; Dioxolanes; Female; Half-Life; HIV-1; Injections, Intravenous; Macaca mulatta; Mass Spectrometry; Metabolic Clearance Rate; Molecular Structure; Reference Standards; Reproducibility of Results; Thymine