Cundy K C, Sueoka C, Lynch G R, Griffin L, Lee W A, Shaw J P
Gilead Sciences, Inc., Foster City, California 94404, USA.
Antimicrob Agents Chemother. 1998 Mar;42(3):687-90. doi: 10.1128/AAC.42.3.687.
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.
在比格犬静脉内、腹腔内和口服给予抗人免疫缺陷病毒核苷酸类似物9-[(R)-2-(膦酰甲氧基)丙基]腺嘌呤（PMPA）后，测定了其药代动力学、生物利用度和代谢情况。空腹雄性比格犬（n = 5）用五肽胃泌素预处理，然后通过静脉内和口服途径接受PMPA（10 mg/kg体重），两次给药之间有1周的洗脱期。另一组雄性犬通过静脉内（1 mg/kg；n = 5）和腹腔内（10 mg/kg；n = 3）途径接受单次剂量的PMPA，两次给药之间有1周的洗脱期。给药后48小时内，通过荧光衍生化和高效液相色谱法（HPLC）测定血浆和尿液中PMPA的浓度。在一只长期留置胆汁插管的犬中评估了PMPA的代谢或胆汁排泄潜力。静脉内给予[14C]PMPA（10 mg/kg；55 μCi/kg）后48小时内，间隔收集尿液、粪便和胆汁。静脉注射后血浆中PMPA的浓度最好用开放二室模型描述，终末半衰期约为10小时。PMPA以原形经尿液排泄（70%）；粪便（0.42%）或胆汁（0.26%）中的回收率可忽略不计。该物种中PMPA的血浆清除率（0.28±0.05升/小时/千克）显著高于肾小球滤过率，提示PMPA存在肾小管主动分泌。基于放射性流动检测的HPLC法，在尿液、粪便或胆汁中未观察到[14C]PMPA的代谢产物。给药后48小时后，其余剂量可能以原形经尿液排泄。口服和腹腔内给予10 mg/kg的PMPA后，观察到的平均±标准差生物利用度分别为17.1%±1.88%和73.5%±10.5%。
