PHARMACOKINETICS AND BIOAVAILABILITY OF THE ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS NUCLEOTIDE ANALOG 9-[(R)-2-(PHOSPHONOMETHOXY)PROPYL]ADENINE (PMPA) IN DOGS

The pharmacokinetics, bioavailability, and metabolism of the anti-huma n immunodeficiency virus nucleotide analog 9[(R)-2-(phosphonomethoxy)p ropyl]adenine (PMPA) mere determined in beagle dogs following intraven ous, 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 per iod of 1 week between doses, A further group of male dogs received PMP A as a single dose via the intravenous (1 mg/kg; n = 5) and the intrap eritoneal (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-performa nce liquid chromatography (HPLC). The potential for metabolism or bili ary 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 [C-14]PMPA (10 mg/kg ; 55 mu Ci/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 negligi ble, The plasma clearance of PMPA (0.28 +/- 0.05 liter/h/kg) was subst antially greater than the glomerular filtration rate in this species, suggesting active tubular secretion of PMPA, No metabolites of [C-14]P MPA were observed in urine, feces, or bile on the basis of HPLC,vith r adioactive flow detection, The remainder of the dose was probably excr eted unchanged in urine beyond 48 h postdosing, The mean a standard de viation observed bioavailabilities of PMPA following oral and intraper itoneal administration at 10 mg/kg were 17.1% +/- 1.88% and 73.5% +/- 10.5%, respectively.