ABSTRACT
The effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant cytochrome P450 2C9.1 microsomes (CYP2C9.1) was studied. The 7-hydroxylation metabolism of S-warfarin was inhibited by as low as 0.1 vol% (17 mM) ethanol. Ethanol decreased the V(max)/K(m) and V(max) values of S-warfarin metabolism in a concentration-dependent manner, but the K(m) value was unchanged by ethanol. The inhibitory effect of ethanol on the 4'-hydroxylation metabolism of diclofenac was not observed even at 1.0 vol% (170 mM) ethanol. Ethanol at a concentration of 3.0 vol% (510 mM) increased the K(m) value of diclofenac metabolism without changes in the V(max), which indicates that diclofenac 4'-hydroxylation by CYP2C9.1 was competitively inhibited by ethanol. S-Warfarin metabolism by CYP2C9.1 was more sensitive to ethanol than diclofenac metabolism. These results suggest that ethanol inhibits the metabolism by CYP2C9.1 in a substrate-dependent manner.
