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

Absorption, distribution and excretion of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a novel gastric prokinetic drug, were studied with C-14-labeled drug in male and female rats mainly after a single oral administration. Plasma concentration and excretion following oral administration of [C-14]mosapride were also investigated in dogs and monkeys of both sexes. The main experimental dose was 10 mg/kg. After oral administration, [C-14]mosapride radioactivity was rapidly absorbed through the intestinal tract. In male rats, concentration of plasma radioactivity reached the maximum (C(max); 1410 ng eq./ml) 1 h after administration and decreased biphasically with half-lives of about 2 h in alpha-phase (t1/2alpha) and in beta-phase (t1/2beta) of about 8 h. t1/2beta was virtually constant in the dose range from 1 mg/kg to 100 mg/kg, and the area under the plasma concentration-time curve (AUC) was proportional to the dose. In female rates, biphasic plasma concentration-time profile with similar half-lives was also observed, but C(max) (2070 ng eq./ml) and AUC were larger than those in male rats, suggesting the sex difference in pharmacokinetics. In dogs and monkeys, C(max)s of plasma concentration were about 1000 ng eq./ml and 2000-3000 ng eq./ml, respectively, and sex difference was not observed Plasma concentrations declined in a biphasic manner and t1/2alpha and t1/2beta were about 4 h and 15 h in dogs and about 3 h and 10 h in monkeys, respectively. The [C-14]mosapride radioactivity was distributed to many tissues including the stomach and small intestine at the higher concentration, while to the brain and eye ball at the lower concentration than the plasma in male rats. Radioactivities in most tissues decreased essentially in parallel with those in plasma. In pregnant rats, concentrations of radioactivity in fetus were a little higher than those in the maternal plasma. In lactating rats, milk radioactivity concentrations were about 5 times higher than corresponding plasma concentrations, and both of them decreased with similar half-lives. Mosapride was bound to serum protein of various animal species, albumin and alpha1-acid glycoprotein, in about 93-99%. After oral administration in rats, about 40% of dosed radioactivity was excreted into urine and about 60% into feces via bile. Neither dose dependency nor sex differences was observed in excretion. In dogs, about 20% of dosed radioactivity was recovered in urine and about 70% in feces. In monkeys, recoveries in urine and feces were about 60 and 30% of dose respectively.