In vivo oxidative cleavage of a pyridine-carboxylic acid ester metabolite of nifedipine.
Biochem Pharmacol
; 38(23): 4213-6, 1989 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-2597191
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nifedipino
Limite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
1989
Tipo de documento:
Article
País de afiliação:
Holanda
País de publicação:
Reino Unido