Vincent S H, Painter S K, Krieter P A, Colletti A E, Lyszack E, Rosegay A, Dean D, Luffer-Atlas D, Miller R R, Cioffe C, Chiu S H
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA.
Drug Metab Dispos. 1996 Dec;24(12):1369-77.
L-683,845 is an orally active inhibitor of human leukocyte elastase. Its disposition was studied in rats and rhesus monkeys after dosing with a 3H- or 14C-labeled compound intravenously at 5 mg/kg and orally at 10 mg/kg. L-683,845 exhibited different pharmacokinetics in these two species. In rats, L-683,845 was well-absorbed after oral dosing, with a maximum concentration of 6 microg/ml at 2 hr and bioavailability of approximately 100%. After intravenous dosing, it was cleared slowly at approximately 3 ml/min/kg, with a terminal half-life of approximately 7 hr and a volume of distribution at steady-state of 1 liter/kg. After both intravenous and oral dosing, L-683,845 comprised 50-95% of plasma radioactivity. About 75% of the intravenous and 87% of the oral dose were recovered in the feces as parent and/or conjugates, with the remaining fraction recovered in the urine as polar components. In rhesus monkeys, maximum concentration after oral dosing was only 0.25 microg/ml, and bioavailability was 50%. Plasma clearance was 8-fold higher, at 23 ml/min/kg, and volume of distribution at steady-state larger, at 2 liters/kg, than in rats. The terminal half-life of L-683,845 could not be determined accurately after intravenous dosing, but seemed to be long in orally dosed animals, approximately 13 hr. Intact L-683,845 was a minor component in plasma comprising only approximately 20% of the radioactivity at most time points. Moreover, persistent levels of radioactivity were detected in plasma and urine of rhesus monkeys even at 1-month postdose, and > or = 25% of the radioactivity in plasma was irreversibly bound to proteins at the later time points. Recovery of the radioactivity was incomplete, with only 77% of the intravenous and 43% of the oral dose recovered over a 4-day period. L-683,845-derived radioactivity distributed to all major rat tissues, with highest levels in the liver followed by the small intestine, adrenals, kidneys, and lungs. Radioactivity concentrations in the liver were high even at 24 hr, 22.7 microg eq/g. A large portion of the intravenous dose was recovered in the small intestine, approximately 40% at 2 hr, indicating rapid and extensive biliary excretion. L-683,845 was metabolized primarily to the acyl glucuronide, which was very unstable in rat plasma, and was subject to hydrolysis to L-683,845 and rearrangement. The glucuronide and L-683,845 were degraded in rat plasma by opening the beta-lactam ring and loss of the C4 substituent followed by decarboxylation to give an olefin and/or decomposition to the monosubstituted urea. Based on inhibition by organophosphorus compounds, it is speculated that their degradation is catalyzed by a type B esterase.
L-683,845是一种口服活性人白细胞弹性蛋白酶抑制剂。给大鼠和恒河猴静脉注射5mg/kg的3H或14C标记化合物以及口服10mg/kg后，对其处置情况进行了研究。L-683,845在这两个物种中表现出不同的药代动力学特征。在大鼠中，口服给药后L-683,845吸收良好，2小时时的最大浓度为6μg/ml，生物利用度约为100%。静脉给药后，其清除缓慢，约为3ml/(min·kg)，终末半衰期约为7小时，稳态分布容积为1L/kg。静脉给药和口服给药后，L-683,845占血浆放射性的50% - 95%。约75%的静脉给药剂量和87%的口服给药剂量以原形和/或结合物形式在粪便中回收，其余部分以极性成分形式在尿液中回收。在恒河猴中，口服给药后的最大浓度仅为0.25μg/ml，生物利用度为50%。血浆清除率比大鼠高8倍，为23ml/(min·kg)，稳态分布容积比大鼠大，为2L/kg。静脉给药后L-683,845的终末半衰期无法准确测定，但在口服给药的动物中似乎较长，约为13小时。完整的L-683,845在血浆中是次要成分，在大多数时间点仅占放射性的约20%。此外，即使在给药后1个月，在恒河猴的血浆和尿液中仍检测到放射性持续存在，在后期时间点血浆中≥25%的放射性与蛋白质不可逆结合。放射性回收不完全，在4天内仅回收了77%的静脉给药剂量和43%的口服给药剂量。L-683,845衍生的放射性分布到大鼠的所有主要组织中，肝脏中的水平最高，其次是小肠、肾上腺、肾脏和肺。即使在24小时时，肝脏中的放射性浓度也很高，为22.7μg eq/g。静脉给药剂量的很大一部分在小肠中回收，2小时时约为40%，表明胆汁排泄迅速且广泛。L-683,845主要代谢为酰基葡糖醛酸，其在大鼠血浆中非常不稳定，会水解为L-683,845并发生重排。葡糖醛酸和L-683,845在大鼠血浆中通过打开β-内酰胺环和失去C4取代基，随后脱羧生成烯烃和/或分解为单取代脲而降解。基于有机磷化合物的抑制作用，推测它们的降解是由B型酯酶催化的。
