Contribution of three CYP3A isoforms to metabolism of R- and S-warfarin.
Effective coumadin (R/S-warfarin) therapy is complicated by inter-individual variability in metabolism. Recent studies have demonstrated that CYP3A isoforms likely contribute to patient responses and clinical outcomes. Despite a significant focus on CYP3A4, little is known about CYP3A5 and CYP3A7 metabolism of warfarin. Based on our studies, recombinant CYP3A4, CYP3A5 and CYP3A7 metabolized R- and S-warfarin to 10- and 4'-hydroxywarfarin with efficiencies that depended on the individual enzymes. For R-warfarin, CYP3A4, CYP3A7, and CYP3A5 demonstrated decreasing preference for 10-hydroxylation over 4'-hydroxylation. By contrast, there was no regioselectivity toward S-warfarin. While all enzymes preferentially metabolized R-warfarin, CYP3A4 was the most efficient at metabolizing all reactions. Individuals, namely African-Americans and children, with higher relative levels of CYP3A5 and/or CYP3A7, respectively, compared to CYP3A4 may metabolize warfarin less efficiently and thus may require lower doses and be at risk for adverse drug-drug interactions related to the contributions of the respective enzymes.
Jones
Drew R
DR
Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205, USA.
Kim
So-Young
SY
Boysen
Gunnar
G
Yun
Chul-Ho
CH
Miller
Grover P
GP
D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001711:Biotransformation; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007536:Isomerism; D007700:Kinetics; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D014859:Warfarin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
D000925:Anticoagulants; D011994:Recombinant Proteins; C059853:4'-hydroxywarfarin; D014859:Warfarin; C065719:10-hydroxywarfarin; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human