PHARMACOKINETICS AND ORAL BIOAVAILABILITY OF EXOGENOUS MELATONIN IN PRECLINICAL ANIMAL-MODELS AND CLINICAL IMPLICATIONS

A review of the literature indicates that the absolute oral bioavailab ility of exogenous melatonin in humans or in preclinical animal models has not been adequately characterized; hence, this study was undertak en. Pharmacokinetics of melatonin was studied in rats, dogs, and monke ys following intravenous and oral administrations, and the absolute or al bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life o f 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 mo nkeys. 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%, suggesti ng the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decrea sed to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs. In vitro permeability studies with CACO-2 cel ls 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.