Drug-drug interactions play an important role in clinical adverse events due to the wide prevalence of multi-drug therapies. The human cytochrome P450 4F (CYP4F) subfamily of enzymes has recently been demonstrated to play a significant role in the metabolism of both endogenous compounds, including arachidonic acid and leukotrienes B4 (LTB4), and drugs/nutrients, including pafuramidine, fingolimod, and vitamin E. However, the role of CYP4F enzymes in mediating potential drug interactions remains uncharacterized. Numerous clinically significant adverse interactions, including major and fatal bleeding episodes, have been reported between the widely-prescribed cholesterol-lowering agents, the 'statins', and the anticoagulant warfarin. Co-administration of these drugs is expected to be on the rise due in part to the purported pleiotropic effects of statins. An improved understanding of the molecular mechanisms underlying the statin-warfarin interaction will provide necessary scientific basis and methodologies to develop an interaction-free statin-warfarin combination, and allow enactment of pertinent regulatory measures limiting certain high-risk statin-warfarin combinations to be prescribed to hundreds of thousands of people each year, which has great public health importance. The long-term goal of the PI's research program is to further our understanding of the pharmacologic and physiologic role of the human CYP4F enzymes. The specific goal of the proposed research is to develop a mechanistic understanding of the role of CYP4F2 in the interaction between statins and warfarin. An innovative and translational experimental approach will be employed to test the central hypothesis that certain statins induce CYP4F2-mediated vitamin K1 metabolism and potentiate the anticoagulant effect of warfarin in humans. Novel methodologies, including a mass spectrometry (MS)-based quantitative proteomic approach for protein quantification, a marker substrate activity assay for CYP4F2, and a double-blind, randomized, placebo-controlled, 2-period cross-over clinical study will be utilized to address key issues regarding 1) the deactivation of vitamin K1 upon ?-hydroxylation by CYP4F2; 2) the induction of CYP4F2 protein expression and enzymatic activity by statin treatment; and 3) the clinical relevance of the effect of statins on warfarin anticoagulation efficacy. Results obtained from the proposed translational research will serve as a foundation for understanding the pharmacologic and physiologic role of CYP4F enzymes, and will provide important information useful in the development of safer statins, and a mechanism by which approved statins can be rank-ordered according to their CYP4F2-inducing potential to guide warfarin dosage adjustment when administered concomitantly. The proposed work has the following specific aims: 1) identify and characterize the vitamin K1 metabolite (K1-?-OH) generated by CYP4F2; 2) determine the induction profiles of statins towards CYP4F2 in HepG2 cells and primary human hepatocytes; and 3) assess the influence of statin treatment on the anticoagulant effect of warfarin in healthy volunteers.

Public Health Relevance

Drug-drug interactions play an important role in clinical adverse events due to the wide prevalence of multi-drug therapy. In spite of numerous reports of clinically significant adverse interactions, the co-medication of warfarin and statins has drastically expanded in the US over the last decades. This proposal seeks to demonstrate a novel molecular mechanism for the statin-warfarin interaction and provide a pathway to develop an interaction-free statin-warfarin combination.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Okita, Richard T
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University of Kansas Lawrence
Schools of Pharmacy
United States
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