Pharmacokinetics of the gastrokinetic agent mosapride citrate after intravenous and oral administrations in rats.
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) were investigated in rats of both sexes. Plasma levels of mosapride and its des-4-fluorobenzyl metabolite (M-1) were determined after an intravenous dose of 2 mg/kg or an oral dose of 10 mg/kg. There were marked sex-related differences in the mean plasma concentration-time profiles of mosapride after single intravenous and oral administration. After oral administration, the Cmax of the unchanged mosapride in male rats (44 ng/ml) was approximately 1/18 of that in female rats (788 ng/ml). The Cmax of M-1 (277 ng/ml) was 6 times higher than that of mosapride in males, while the Cmax in females (149 ng/ml) was 1/5 of that of mosapride. Male rats exhibited more rapid elimination (t1/2 of 1.9 h) than females (2.8 h). These sex-dependent pharmacokinetics of mosapride in rats would be explained by two reasons: different activity of hepatic drug-metabolizing enzymes to M-1 and partly different distribution volume of mosapride. Oral bioavailability of mosapride was 7% of the dose in males and 47% in females, suggesting extensive first-pass metabolism in males. Once daily 7-day multiple administration did not affect the pharmacokinetics of mosapride both in male and female rats.
Sakashita
M
M
Department of Pharmacokinetics, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Mizuki
Y
Y
Hashizume
T
T
Yamaguchi
T
T
Miyazaki
H
H
Sekine
Y
Y
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; C062720:mosapride