Stereoselectivity in the Hydroxylation of Propafenone Enantiomers in Mouse Hepatic Microsomes

• Published in: Biological & pharmaceutical bulletin 1994/04/15, Vol.17(4), pp.531-534
• Main Authors: MORITA, Kunihiko, MIZUOCHI, Masaharu, YAMAJI, Akira, YOKOYAMA, Teruyoshi
• Format: Article
• Language: English
• Subjects: Animals; Antiarythmic agents; Biological and medical sciences; Cardiovascular system; Chromatography, High Pressure Liquid; cytochrome P-450; Cytochrome P-450 Enzyme System - metabolism; drug-metabolism; Hydroxylation; Kinetics; Male; Medical sciences; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; mouse hepatic microsome; Oxidation-Reduction; Pharmacology. Drug treatments; Phenobarbital - pharmacology; Propafenone - analogs & derivatives; Propafenone - metabolism; propafenone 5-hydroxylation; propafenone enantiomer; Stereoisomerism; stereoselectivity
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.17.531

Stereoselectivity in the oxdative metabolism of propafenone (PPF) enantiomers to 5-hydroxypropafenone was studied with untreated and inducer-treated mouse hepatic microsomes. In the untreated microsomes, Lineweaver-Burk plots of the 5-hydroxylation of R (-)- and S(+)-PPF were single lines, and the intrinsic clearance (Vmax/Km) value of R (-)-PPF was 1.3-fold higher than that of S(+)-PPF. When racemic PPF was used as a substrate, the plot was shifted to the upper region, in comparison with that estimated from the sum of the individual 5-hydroxylase activities of each enantiomer, suggesting enantiomer/enantiomer interaction. In phenobarbital-induced microsomes, the Lineweaver-Burk plot for R(-)-PPF was a single line, but that for S (+)-PPF was biphasic. When racemic PPF was used as a substrate, the plot was biphasic and was shifted to the upper region in comparison with that estimated from the sum of the individual 5-hydroxylase activities of each enantiomer. The observed value of intrinsic clearance of the PPF racemate at lower concentrations (Vmax1/Km1) was consistent with the estimated value, suggesting no interaction between R(-)- and S(+)-PPF. These findings indicate that most of the 5-hydroxylation of R(-)- and S(+)-PPF is catalyzed by common cytochrome P-450 species, but a part of S(+)-PPF 5-hydroxylation is catalyzed by another phenobarbital inducible cytochrome P-450 species, particularly at lower substrate concentrations.