Tiropramide and metabolites in blood and plasma after intravenous or peroral administration of 14C-tiropramide to the rat.

The study was performed with 14C-tiropramide hydrochloride (O-(2-diethylamino-ethyl)-N-benzoyl-[DL-U-14C-tyrosyl]-dipropyl-amide hydrochloride) with a specific activity of 466.16 muCi/mmol. The substance was administered in single i.v. doses of 4 mg/kg to 18 male and 18 female rats or p.o. doses of 10 mg/kg to 16 male and 16 female rats. The radioactivity in blood and plasma was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. After i.v. administration the parent substance tiropramide and 5 metabolites were identified in plasma. Tiropramide was the most abundant substance with an AUC equal to 51% of the AUC of total radioactivity. After p.o. administration the parent tiropramide and 5 metabolites were identified. Tiropramide was the most abundant substance till the 1st h. Then the metabolite CR 1098 ((+-)a-benzoylamino-4-(2-ethylamino-ethoxy)-N, N-dipropyl-benzenepropanamide) prevailed. The Cmax of tiropramide was reached at 0.5 h with 1183 nmol/l. The AUC of tiropramide was 19% of the AUC of total radioactivity. It appears that after p.o. administration the biotransformation of tiropramide is more intense than after i.v. administration. The absolute bioavailability of total radioactivity calculated on the ratio between the p.o. and i.v. AUC was 0.67, that of tiropramide was 0.23. The difference between the absolute bioavailability of total radioactivity and that of tiropramide is probably due to a first-pass effect and a more intense biotransformation of the substance after p.o. administration.