Biotransformation of nimodipine in rat, dog, and monkey

Abstract

14C-labelled (+/-) 3-isopropyl5-(2-methoxyethyl)1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate (nimodipine, Bay e 9736, Nimotop; CAS 66085-59-4) was administered orally to rat, dog, and monkey (each 5, 10, or 20 mg/kg) and intraduodenally to rat (5 mg/kg). Urine was collected over a period of 24 h (bile 6 h). Dog bile was obtained from the gall bladder 4 h after oral dosing. Rat plasma was taken 1 h p. appl. of the unlabelled compound and additionally at different times following administration of [14C]nimodipine. The metabolite profiles in the excreta were established by TLC (radioscan/autoradiography). The unchanged drug was neither detectable in urine nor in bile, but was present in rat plasma. Nimodipine was extensively metabolized. 18 metabolites were isolated by LC, HPLC, and preparative TLC and identified by comparison with the reference substances using two-dimensional TLC, HPLC, GC/radio-GC, 1H-NMR-spectroscopy, MS, and GC/MS. About 75% of the renally excreted biotransformation products, more than 50% of the metabolites present in the bile (rat, dog) and approx. 80% of the plasma metabolites (rat only) have been identified. The large number of metabolites was produced by some common biotransformation reactions: dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, oxidative O-demethylation and subsequent oxidation of the resulting primary alcohol to the carboxylic acid, hydroxylation of the methyl groups at 2- or 6-position, hydroxylation of one methyl group of the isopropyl ester moiety, reduction of the aromatic nitro group, and glucuronidation as phase II-reaction.