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
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.
Available from: Srinivasan Shanmugam
- "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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ABSTRACT: Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue for patients and health insurance authorities due to awareness of adverse drug event. In this study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic parameters of theophylline changed significantly when the drug was administered after five consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration of theophylline delayed when the drug was administered after the pretreatment with CoQ10. Maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly. Therefore, although CoQ10 is generally considered a safe dietary supplement, it appears that patients on theophylline therapy should use caution when they take CoQ10.
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ABSTRACT: Green tea (Camellia sinensis), and CoQ(9 )when given to Wistar rats produced a partial reversal on reserpine induced oxidative stress and liver damage. Green tea, with its abundant polyphenol (-)Epigallocatechin 3-gallate (ECGC) and other catechins, is known for its antioxidative characteristics influencing lipid metabolism. Ubiquinone, abundant in heart muscle, is also a potent antioxidant with known effects in numerous pathologies. However the combined effect of ECGC and ubiquninone has not been reported. In the present study we found that green tea extract, when given in combination with CoQ(9) to Wistar rats subjected to oxidative stress, showed a statistically significant antioxidative effect. Liver cholesterol level in rats receiving combination treatment was also significantly lower than control or rats receiving green tea extract alone. Reserpine induced liver damage in Wistar rats was also partially reversed by a treatment of green tea extract when combined with CoQ(9). These results may have important clinical implications and may be extrapolated for the treatment of patients suffering from liver damage due to hepatitis B/C or liver cirrhosis.
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ABSTRACT: To summarize, warfarin is the drug mostly commonly reported to interact with supplements. However, reporting of interactions is sporadic and sometimes contradictory. For example, Ginseng may increase the clearance of warfarin, but trial evidence is conflicting. Co-enzyme Q10 and Ginkgo biloba may not interfere with warfarin activity significantly, but further study is necessary. St. John's wort likely increases hepatic clearance of warfarin and phenprocoumon, thereby decreasing the anti-coagulant effect of these coumarins.
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