Shaw J P, Sueoko C M, Oliyai R, Lee W A, Arimilli M N, Kim C U, Cundy K C
Gilead Sciences, Inc., Foster City, California 94404, USA.
Pharm Res. 1997 Dec;14(12):1824-9. doi: 10.1023/a:1012108719462.
A series of prodrugs designed to enhance the oral bioavailability of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA; 1) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) esters 3-9. The in vitro biological stability and in vivo pharmacokinetics of these prodrugs were evaluated to support selection of a prodrug candidate for clinical evaluation.
The in vitro biological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma and liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detection. Oral bioavailability of PMPA from each prodrug was determined in fasted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were compared to historical data for intravenous PMPA.
All prodrug were rapidly hydrolyzed in dog plasma and tissues (t1/2 < 60 min). In fasted beagle dogs, bis-[(pivaloyloxy)methyl] PMPA (bis-POM PMPA) 2 had the highest oral bioavailability as PMPA (37.8 +/- 5.1%). The oral bioavailabilities of PMPA from bis-(alkoxycarbonyloxymethyl) esters ranged from 16.0% to 30.7% and PMPA was the major metabolite formed.
There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxy-carbonyloxymethyl) PMPA 8 (t1/2 < 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.
已合成了一系列旨在提高抗逆转录病毒药物9-[(R)-2-(膦酰甲氧基)丙基]腺嘌呤（PMPA；1）口服生物利用度的前药，包括双-(酰氧基甲基)酯2和一系列双-(烷氧羰基氧基甲基)酯3 - 9。对这些前药的体外生物稳定性和体内药代动力学进行了评估，以支持选择一种前药候选物进行临床评估。
在犬组织（肠匀浆、血浆和肝匀浆）中检测前药的体外生物稳定性。使用带紫外检测的反相高效液相色谱法，根据前药的消失情况测定表观半衰期。在禁食的比格犬中测定每种前药中PMPA的口服生物利用度。血浆中PMPA的浓度通过荧光衍生化后的高效液相色谱法测定。将前药的数据与静脉注射PMPA的历史数据进行比较。
所有前药在犬血浆和组织中均迅速水解（t1/2 < 60分钟）。在禁食的比格犬中，双-[(新戊酰氧基)甲基]PMPA（双-POM PMPA）2作为PMPA的口服生物利用度最高（37.8±5.1%）。双-(烷氧羰基氧基甲基)酯中PMPA 的口服生物利用度在16.0%至30.7%之间，且PMPA是形成的主要代谢产物。
双-(烷氧羰基氧基甲基)酯前药的口服生物利用度与肠道稳定性之间存在相关性（r2 = 0.96）。亲脂性（log P）不是口服生物利用度的良好预测指标。在犬肠匀浆中最不稳定的前药，双-(正丁氧羰基氧基甲基)PMPA 5和双-(新戊氧羰基氧基甲基)PMPA 8（t1/2 < 5分钟）的口服生物利用度最低。基于良好的口服生物利用度（30.1%）、化学稳定性和肠道稳定性，双-(异丙氧羰基氧基甲基)PMPA（双-POC PMPA）4被选为临床评估的候选物。
