In vivo oxidative cleavage of a pyridinecarboxylic acid ester metabolite of nifedipine

Abstract

The pharmacokinetics of the primary pyridine metabolite of nifedipine (2,6-dimethyl-4-(2-nitrophenyl)-3, 5-pyridinecarboxylic acid dimethylester) (M-0) and its [ 2H 6]dimethylester analog ([ 2H 6]M-0) were studied in male rats. A large, 5.8-fold deuterium isotope effect for the formation clearance of the monomethylester (M-1) was observed, which is strongly indicative for an oxidative reaction mechanism involving the abstraction of a hydrogen atom, presumably by cytochrome P-450. M-0 exhibited a high systemic blood clearance (104 ± 27 ml/min/kg) (mean ± SD) which was not significantly influenced by deuterium substitution (125 ± 13 ml/min/kg). Its systemic clearance is presumably flow limited, and extrahepatic metabolism can be anticipated. The major metabolic pathway for M-0 in male rats seems to be a direct oxidation at the 2-methyl position and subsequently a rapid conversion of the unstable 2-hydroxymethyl-dimethylester to the lactone of the monomethylester (M-2), as has been shown by others in vitro. Non-oxidative ester cleavage of M-0 in our rats was negligible. Deuterium substitution of M-0 at the ester methyl groups induced “metabolic switching” in favor of the direct oxidation of M-0 to M-2.