| Effect of coenzyme Q10 on warfarin hydroxylation in rat and human liver microsomes. | |
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MedLine Citation:
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PMID: 15853759 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Our previous animal study has suggested that the accelerated metabolism of warfarin enantiomers with concurrent coenzyme Q(10) (CoQ(10)) treatment accounts for the reduced anticoagulant effect of warfarin in rats. The present study was to assess the effect of CoQ(310) on individual hydroxylation pathways of the in vitro microsomal metabolism of warfarin enantiomers and to extrapolate in vitro data to in vivo situation. The effect of the antioxidant CoQ(10) on the hydroxylation of warfarin enantiomers was examined using rat and human liver microsomes. Based on the in vitro kinetic data, together with the information retrieved from the literature, the magnitude of warfarin-CoQ(10) interaction in man was quantitatively predicted. In rat liver microsomes, CoQ(10) exhibited a selective activation effect on the 4'-hydroxylation of S-warfarin, with a K(A) value (i.e. dissociation constant of the enzyme-activator complex) being one third and one fifth of those for the 6- and 7-hydroxylation, respectively. The activation effect of CoQ(10) was selective towards the 6- and 7-hydroxylation of R-warfarin at low substrate concentrations, but towards the 4'-hydoxylation of the R-enantiomer at high substrate concentrations. In human liver microsomes, CoQ(10) was a selective activator of the 7-hydroxylation of both R- and S-enantiomers of warfarin, with K(A) values being half to one twelfth of those for the other pathways. A relatively accurate prediction was made for the increase in the total and hepatic clearance of both S- and R-warfarin in rats with concurrent CoQ(10) treatment based on their respective overall hydroxylation, when the active transport of CoQ(10)into the hepatocytes was taken into consideration. In man, one would expect about 32% and 17% increase in the total clearance of S- and R-warfarin, respectively, with coadministration of 100 mg CoQ(10). In both species, CoQ(10) had enzyme activation effect, which appeared to be regioselective but not stereoselective, on the formation of the phenolic metabolites of warfarin enantiomers. A moderate increase in the total clearance of warfarin enantiomers could occur with coadministration of CoQ(10)in humans. |
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Authors:
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Qingyu Zhou; Shufeng Zhou; Eli Chan |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Current drug metabolism Volume: 6 ISSN: 1389-2002 ISO Abbreviation: Curr. Drug Metab. Publication Date: 2005 Apr |
Date Detail:
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Created Date: 2005-04-27 Completed Date: 2005-07-15 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 100960533 Medline TA: Curr Drug Metab Country: Netherlands |
Other Details:
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Languages: eng Pagination: 67-81 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antioxidants / chemistry*, metabolism Coenzymes Humans Hydroxylation Male Microsomes, Liver / enzymology*, metabolism Rats Rats, Sprague-Dawley Ubiquinone / analogs & derivatives*, chemistry*, metabolism Warfarin / antagonists & inhibitors, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Coenzymes; 1339-63-5/Ubiquinone; 303-98-0/coenzyme Q10; 81-81-2/Warfarin |
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