PHARMACOKINETICS AND BIOAVAILABILITY OF THE ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS NUCLEOTIDE ANALOG 9-[(R)-2-(PHOSPHONOMETHOXY)PROPYL]ADENINE (PMPA) IN DOGS
Kc. Cundy et al., PHARMACOKINETICS AND BIOAVAILABILITY OF THE ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS NUCLEOTIDE ANALOG 9-[(R)-2-(PHOSPHONOMETHOXY)PROPYL]ADENINE (PMPA) IN DOGS, Antimicrobial agents and chemotherapy, 42(3), 1998, pp. 687-690
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.