Metabolism of a new dihydropyridine calcium antagonist in rats and dogs

1. The metabolism of a new dihydropyridine calcium channel blocker was studied in rats and dogs. The drug was extensively metabolized by both species after oral dosing. Metabolites were detected by two-dimensional t.l.c. after dosing with the ¹⁴C-labelled drug. Urinary metabolite patterns were quantitatively different in rats and dogs.

2. Ten metabolites were isolated from urine, bile and liver homogenate of male or female rats, and identified.

3. The main metabolic pathway was oxidation of the dihydropyridine moiety to the pyridine form, followed by the hydrolysis of the ester, oxidation of the methyl group at the 6-position, and oxidation of the isopropyl group. Other pathways were hydrolysis of the 3-isopropyl ester or 5-methyl ester group to the dihydropyridine monocarboxylic acid (M-2 and M-10, respectively).

4. The drug was metabolized in rats stereoselectively. M-2 and M-10 isolated from rat female urine were analysed by chiral stationary-phase h.p.l.c. and were mainly the enantiomers derived from (-)- and (+)-drug, respectively.