Qingyu Zhou, Shufeng Zhou and Eli Chan Pages 67 - 81 ( 15 )
Our previous animal study has suggested that the accelerated metabolism of warfarin enantiomers with concurrent coenzyme Q10 (CoQ10) treatment accounts for the reduced anticoagulant effect of warfarin in rats. The present study was to assess the effect of CoQ10 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 CoQ10 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-CoQ10 interaction in man was quantitatively predicted. In rat liver microsomes, CoQ10 exhibited a selective activation effect on the 4-hydroxylation of S-warfarin, with a KA 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 CoQ10 was selective towards the 6- and 7-hydroxylation of Rwarfarin at low substrate concentrations, but towards the 4-hydoxylation of the R-enantiomer at high substrate concentrations. In human liver microsomes, CoQ10 was a selective activator of the 7-hydroxylation of both R- and Senantiomers of warfarin, with KA 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 CoQ10 treatment based on their respective overall hydroxylation, when the active transport of CoQ10 into the hepatocytes was taken into consideration. In man, one would expect about 32% and 17% increase in the total clearance of S- and Rwarfarin, respectively, with coadministration of 100 mg CoQ10. In both species, CoQ10 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 CoQ10 in humans.
warfarin enantiomers, coenzyme, liver microsomes, in vitro metabolic study
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543,Republic of Singapore.