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标题：Stereoselectivity in the Hydroxylation of Propafenone Enantiomers in Mouse Hepatic Microsomes
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作者：Kunihiko MORITA ; Masaharu MIZUOCHI ; Akira YAMAJI 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1994
卷号：17
期号：4
页码：531-534
DOI：10.1248/bpb.17.531
出版社：The Pharmaceutical Society of Japan
摘要：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.
关键词：propafenone enantiomer;stereoselectivity;cytochrome P-450;propafenone 5-hydroxylation;drug-metabolism;mouse hepatic microsome