Pharmacokinetics of the gastrokinetic agent mosapride citrate after intravenous and oral administrations in dogs and monkeys.

The pharmacokinetics and bioavailability of mosapride citrate ((+-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4- fluorobenzyl)-2-morpholinyl]methyl]benzamide citrate dihydrate, AS-4370, CAS 112885-42-4), a new gastrokinetic agent, were investigated in dogs and monkeys. Plasma levels of mosapride and its des-4-fluorobenzyl metabolite (M-1) were determined after a single intravenous dose (2 mg/kg) or a single oral dose (10 mg/kg). After intravenous administration, mean plasma levels of mosapride in male dogs and monkeys showed biphasic decrease with t1/2 alpha of 0.3 and 0.6 h, and t1/2 beta of 2.4 and 2.4 h, respectively. Mean concentrations of mosapride increased rapidly and reached the maximum 0.5-1 h after oral administration to male dogs and monkeys, followed by quick decrease with t1/2 of 1.5 and 0.9 h, respectively. The Cmax was 207 ng/ml in dogs and 862 ng/ml in monkeys. The Cmaxs of M-1 in both species were virtually equivalent to those of the unchanged drug. Plasma concentration-time profiles and pharmacokinetic parameters of mosapride and M-1 in female dogs and monkeys were similar to those in males, indicating no sex-related differences in the pharmacokinetics of mosapride in these animal species. Oral bioavailability was 8% of the dose in dogs and 14% in monkeys, suggesting the extensive first-pass metabolism of mosapride.