title: Pharmacokinetics and bioavailability of the anti-human immunodeficiency virus nucleotide analog 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc., Foster City, California 94404, USA. Ken_cundy@gilead.com
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: C
authors.initials: C
authors.lastname: Sueoka
authors.forename: G R
authors.initials: GR
authors.lastname: Lynch
authors.forename: L
authors.initials: L
authors.lastname: Griffin
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D000068698:Tenofovir; D000225:Adenine