METABOLISM OF [CARBONYL-C-14] MOSAPRIDE CITRATE AFTER A SINGLE ORAL-ADMINISTRATION IN RATS, DOGS AND MONKEYS

The metabolism of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N- [[4- (4-fluorobenzyl) -2-morpholi-nyl]methyl]benzamide citrate, AS-4370, CAS 112885-42-4) was investigated in rats, dogs and monkeys after a single oral administration. Four metabolites, M-1 to M-4, were isolated from rat urine. Two of them were identified as des-p-fluorobenzyl (M-1) and 5'-oxo-des-p-fluorobenzyl mosapride (M-2) and the other two were considered to be as 3-hydroxy des-p-fluorobenzyl (M-3) and 3-hydroxy 5-oxo-des-p-fluorobenzyl mosapride (M-4) by mass spectrometry and/or nuclear magnetic resonance spectrometry. Metabolites in biological specimens such as plasma and urine after oral administration of [C-14]mosapride in rats, dogs and monkeys were analyzed by thin layer chromatography (TLC). Unchanged mosapride M-1, M-2 and some other metabolites were observed in the plasma of male rats. On the other hand, female rat plasma contained mosapride as the major radioactive component with a small amount of M-1 and little other metabolite(s). In rat urine, irrespective of sex, M-1, M-2, M-3, M-4 and a few other metabolites were observed but the unchanged drug was hardly detected. These facts suggested that the metabolic rate of mosapride was different between sexes in rats. In male rat bile, mosapride, M-1 and polar metabolite(s) were observed In dogs, mosapride and M-1 were observed as major radioactive components plasma, and M-1 was seen also as the major metabolite in urine but unchanged drug was hardly detected Similar results were obtained in monkeys. From these results; mosapride was extensively metabolized and the metabolic clearance seemed to be predominant in the elimination of mosapride from the body, regardless of species or sexes. The sex difference in the metabolic rate of mosapride was thus suggested in rats, but not in dogs and monkeys.