Effect of ethanol on S-warfarin and diclofenac metabolism by recombinant human CYP2C9.1.
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.
Tatsumi
Akitoshi
A
Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, Japan. atatsumi@kobepharma-u.ac.jp
Ikegami
Yuki
Y
Morii
Ryoko
R
Sugiyama
Masatoshi
M
Kadobayashi
Muneo
M
Iwakawa
Seigo
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D011994:Recombinant Proteins; D004008:Diclofenac; D000431:Ethanol; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases