Yeleswaram K, McLaughlin L G, Knipe J O, Schabdach D
Department of Metabolism & Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
J Pineal Res. 1997 Jan;22(1):45-51. doi: 10.1111/j.1600-079x.1997.tb00302.x.
A review of the literature indicates that the absolute oral bioavailability of exogenous melatonin in humans or in preclinical animal models has not been adequately characterized; hence, this study was undertaken. Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs. In vitro permeability studies with CACO-2 cells suggest that melatonin is likely to be well absorbed in humans. In vitro metabolism studies with fresh liver slices from rats as well as human donors were conducted to compare the initial rates of metabolism of melatonin between the two species and the results suggest that the intrinsic clearance of melatonin in humans may be lower than that in rats.
文献综述表明，外源性褪黑素在人类或临床前动物模型中的绝对口服生物利用度尚未得到充分表征；因此，开展了本研究。在大鼠、犬和猴静脉注射和口服给药后研究了褪黑素的药代动力学，并根据血浆浓度-时间曲线下面积计算了褪黑素的绝对口服生物利用度。静脉注射剂量为3 mg/kg（大鼠为5 mg/kg）后，大鼠、犬和猴体内褪黑素的表观消除半衰期分别为19.8分钟、18.6分钟和34.2分钟。口服剂量为10 mg/kg后，大鼠体内褪黑素的剂量标准化口服生物利用度为53.5%，而犬和猴体内则超过100%。此外，大鼠腹腔注射10 mg/kg剂量后，褪黑素的生物利用度为74.0%，表明大鼠体内褪黑素不存在显著的首过肝提取。然而，犬口服1 mg/kg剂量后，褪黑素的口服生物利用度降至16.9%，表明犬体内存在剂量依赖性生物利用度。用Caco-2细胞进行的体外通透性研究表明，褪黑素在人体内可能易于吸收。用大鼠和人类供体的新鲜肝切片进行体外代谢研究，以比较两种物种之间褪黑素的初始代谢速率，结果表明，人体内褪黑素的内在清除率可能低于大鼠。
