title: In vivo oxidative cleavage of a pyridine-carboxylic 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 [2H6]dimethylester analog ([2H6]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.
authors.affiliation: Division of Pharmacology, Leiden University, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Funaki
authors.forename: P A
authors.initials: PA
authors.lastname: Soons
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: D D
authors.initials: DD
authors.lastname: Breimer
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: C058273:DHM 9; D003577:Cytochrome P-450 Enzyme System; D009543:Nifedipine