Stereoselectivity in the Hydroxylation of Propafenone Enantiomers in Mouse Hepatic Microsomes

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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 (V_<max>/K_m) 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 (V_<max1>/K_<m1>) 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.
公益社団法人日本薬学会の論文
1994-04-15

Stereoselectivity in the Hydroxylation of Propafenone Enantiomers in Mouse Hepatic Microsomes

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