Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog
Michiels, M.; Monbaliu, J.; Hendriks, R.; Geerts, R.; Woestenborghs, R.; Heykants, J.
Arzneimittel-Forschung 37(10): 1159-1167
1987
ISSN/ISBN: 0004-4172 PMID: 3435588 Document Number: 301155
The plasma kinetics and tissue distribution of the gastrokinetic (.+-.)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration in rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min .cntdot. kg and 4.7 l/kg in the rat and 4.2 ml/min .cntdot. kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog. After oral administration of 14C-cisapride at 10 mg/kg to rats, highest tissue radioactivity, attained within 15 to 30 min, occurred in the oiver and in the tissues of the gastrointestinal tract. A specific uptake of cisapride was seen in the gastric and intestinal wall. Markedly higher tissue than plasma levels further occurred in the lung, kidney, glandular and lymphatic tissues. Brain radioactivity, marinly due to cisapride, was 2 to 3 times lower than that in plasma. Tissue levels in female rats were generally twice higher than those in male rats. The ratio of tissue to plasma concentrations of radioactivity and unchanged drug were constant with time and there was no evidence of a retention of cisapride or its metabolites due to repeated oral administration at 10 mg/kg. Similarly in dogs, no undue accumulation of cisapride was seen in any tissue of animals treated at up to 40 mg/kg/d for 12 months, and as for plasma, distribution kinetics were proportional in the dose range studied. Placental transfer of radioactivity in rats after single oral (10 mg/kg) or intravenous (5 mg/kg) doses of 14C-cisapride was low. At peak time, 0.8% of the intravenous and 0.4% of the oral dose given to the dams was recovered in the combined foetuses. These small quantities were mainly due to the parent drug, indicating that transition of metabolites through the placenta was even more limited. In lactating dogs, orally doses with 14C-cisapride at 5 mg/kg, milk radioactivity levels were 3 to 4 times, and those of the parent drug on average twice the corresponding concentrations in plasma. Preferentially metabolites were excreted with the milk.