Effect of Coenzyme Q10 on Warfarin Hydroxylation in Rat and Human Liver Microsomes

Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.
Current Drug Metabolism (Impact Factor: 2.98). 05/2005; 6(2):67-81. DOI: 10.2174/1389200053586091
Source: PubMed


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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    • "To date, warfarin is the only prescription drug which demonstrated detrimental outcome with concurrent use of CoQ10. Although exact mechanism of the interaction is not fully elucidated, CoQ10 increases metabolism of warfarin by selective activation of cytochrome P450 enzymes in rat and human liver microsomes, which are also involved in the metabolism of theophylline (Tjia et al., 1996; Zhou et al., 2005; Kaminsky and Zhang 1997). Theophylline is a medication commonly used for the treatment of asthma and chronic obstructive pulmonary disease as a long-term treatment. "
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