Stereoselectivity in the disposition of propafenone enantiomers. The role of hepatic microsomal cytochrome P-450 species and serum alpha1-acid glycoprotein.
Project/Area Number |
05671897
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Research Category |
Grant-in-Aid for General Scientific Research (C)
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Allocation Type | Single-year Grants |
Research Field |
応用薬理学・医療系薬学
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Research Institution | Shiga University of Medical Science |
Principal Investigator |
YAMAJI Akira Shiga Univ.Med.Sci., Dept.Hosp.Pharm., Professor., 医学部, 教授 (10093478)
|
Project Period (FY) |
1993 – 1994
|
Project Status |
Completed (Fiscal Year 1994)
|
Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1994: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1993: ¥1,400,000 (Direct Cost: ¥1,400,000)
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Keywords | Enantiomer / Chiral compound / Propafenone / Drug metabolism / alpha1-acid glycoprotein / α_1酸性糖タンパク質 |
Research Abstract |
Stereoselectivity in the oxidative metabolism of propafenone (PPF) enantiomers to 5-hydroxypro-parenone 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 single line, but that for S (+) -PPF was biphasic. When racemic PPF was used as a substrate, the plot was biphasic and shifted to the upper region in comparison with that estimated from the sum of 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 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 another phenobarbital inducible cytochrome P-450 species, particularly at lower substrate concentrations.
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Report
(3 results)
Research Products
(4 results)