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.
Sakashita
M
M
Department of Pharmacokinetics, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Mizuki
Y
Y
Yamaguchi
T
T
Miyazaki
H
H
Sekine
Y
Y
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; C062720:mosapride