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The pharmacokinetics, bioavailability, and metabolism of the anti-human immunodeficiency virus nucleotide analog 9[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) were determined in beagle dogs following intravenous, intraperitoneal, and oral administration. Fasted male beagle dogs (n = 5) were pretreated with pentagastrin and received PMPA (10 mg/kg of body weight) by the intravenous and oral routes with a washout period of 1 week between doses. A further group of male dogs received PMPA as a single dose via the intravenous (1 mg/kg; n = 5) and the intraperitoneal (10 mg/kg; n = 3) routes, with 1-week washout period between doses. The concentrations of PMPA in plasma and urine were determined over 48 h postdosing by fluorescence derivatization and high-performance liquid chromatography (HPLC). The potential for metabolism or biliary excretion of PMPA was evaluated in a dog with a chronic indwelling bile cannula. Urine, feces, and bile were collected at intervals over 48 h following the intravenous administration of [14C]PMPA (10 mg/kg; 55 microCi/kg). The concentrations of PMPA in plasma after intravenous injection were best described by an open two-compartment model with a terminal half-life of approximately 10 h. PMPA was excreted unchanged in urine (70%); recovery in feces (0.42%) or bile (0.26%) was negligible. The plasma clearance of PMPA (0.28+/-0.05 liter/h/kg) was substantially greater than the glomerular filtration rate in this species, suggesting active tubular secretion of PMPA. No metabolites of [14C]PMPA were observed in urine, feces, or bile on the basis of HPLC with radioactive flow detection. The remainder of the dose was probably excreted unchanged in urine beyond 48 h postdosing. The mean+/-standard deviation observed bioavailabilities of PMPA following oral and intraperitoneal administration at 10 mg/kg were 17.1%+/-1.88% and 73.5%+/-10.5%, respectively.

antimicrobial agents and chemotherapy

Pharmacokinetics and Bioavailability of the Anti-Human Immunodeficiency Virus Nucleotide Analog 9-[( <i>R</i> )2-(Phosphonomethoxy)Propyl]Adenine (PMPA) in Dogs

Pharmacokinetics and Bioavailability of the Anti-Human Immunodeficiency Virus Nucleotide Analog 9-[( R )2-(Phosphonomethoxy)Propyl]Adenine (PMPA) in Dogs