Contribution of Three CYP3A Isoforms to Metabolism of R- and S-Warfarin

Drew      R. Jones; So-Young      Kim; Gunnar      Boysen; Chul-Ho      Yun; Grover      P. Miller

doi:10.2174/187231210792928242

Abstract

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 Swarfarin. 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.

Keywords: CYP3A, hydroxywarafrin, in vitro, metabolism, MS/MS, UPLC, warfarin, CYP3A Isoforms, S-Warfarin, Effective Coumadin, drug-drug interactions, polymorphisms, Multiple cytochrome P450s, baculovirus-infected, recombinant enzyme, CYP3A4, CYP3A5, CYP3A7, R-warfarin, Michaelis-Menten equation, non-specific marker, pharmacogenomic, drug response