The long-term goal of this project is to understand how human genetic variation modifies drug-druginteractions. We focus here on metabolic interactions involving the widely used oral anticoagulant drug,warfarin. Warfarin has, for many decades, provided a model system for studying mechanisms of drug-druginteractions, but no information is available as to the extent to which common polymorphisms in warfarinresponsegenes affect these drug interactions. CYP2C9 genotype is particularly important because thisenzyme governs the metabolic inactivation of the more potent S-enantiomer of the drug. Consequently, thecurrent proposal addresses the central question; How does CYP2C9 genotype modify warfarin druginteractions that have a metabolic basis? This will be accomplished with the following specific aims;
Aim 1 Determine the magnitude of the warfarin-fluconazole inhibitory drug interaction in healthyvolunteers genotyped for CYP2C9*1/ *1, *1/*3 or *3/*3 by measuring warfarin enantiomer AUC, clearance,partial metabolite clearances, and prothrombin time.
Aim 2 Determine the magnitude of the warfarin-rifampin inductive drug interaction in the same genotypedsubject population studied in Aim 1.
Aim 3 Exploit CYP2C9 null systems to determine the role of alternative P450s in S-warfarin clearance insubjects with genetically compromised CYP2C9 activity, and develop in vitro systems to recapitulate the invivo metabolic interactions characterized in Aims 1 and 2.
Aim 4 Synthesize known and suspected inhibitory metabolites of amiodarone, and determine theirinhibitory potency in vitro against P450 enzymes known to contribute to warfarin clearance.
Aim 5 Define, in warfarin patients, the contribution of CYP2C9 genotype, CYP2C8 genotype and steadystateplasma levels of amiodarone and its inhibitory metabolites, to variability in warfarin dose adjustment inpatients receiving combination therapy.
Aims 1 and 2 address the hypothesis that functionally defective CYP2C9 alleles attenuate the warfarinfluconazoleinhibitory interaction and exacerbate the warfarin-rifampin inductive interaction.
Aim 3 addresses the hypothesis that CYP2C9-deficient subjects are at increased risk from metabolic interactionsinvolving CYP3A4.
Aims 4 and 5 address the hypothesis that the magnitude of the warfarin-amiodaronedrug interaction can be predicted using information about the genotype status for CYP2C9, CYP2C8, andthe plasma concentration of circulating inhibitory metabolites of amiodarone.Successful completion of these studies is expected to improve clinical care of warfarin patientsundergoing treatment with P450 inhibitors and inducers by providing a mechanistic framework, incorporatingpharmacogenomic considerations, that will improve guidance of dose adjustment during polytherapy with thiswidely used oral anticoagulant.
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