Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Richard Kim

Abstract

Thromboembolic disorders are a major cause of morbidity and mortality. Therapeutic intervention with anticoagulants and antiplatelets greatly reduces the risk of arterial and venous thrombosis. However, the observed large interindividual variation in responsiveness to these drugs indicates that subsets of patients are not attaining optimal therapy, resulting in either lack of antithrombotic effect or elevated bleeding risk. Recently, single nucleotide polymorphisms (SNPs) have been linked to the variation observed in efficacy and toxicity for many cardiovascular drugs.

Warfarin has been the gold standard anticoagulant for prevention of stroke and thromboembolism in atrial fibrillation (AF) and venous thromboembolism (VTE) patients. SNPs in genes that affect warfarin metabolism (CYP2C9) and response (VKORC1) have an important influence on response and dose, particularly during initiation. Accordingly, we developed and evaluated the clinical utility of a pharmacogenetics-based initiation nomogram in AF and VTE patients which provides safe and optimal anticoagulation therapy irrespective of genetic variation.

The new oral anticoagulant (NOAC) rivaroxaban is highly dependent on the kidney for elimination through glomerular filtration and active tubular secretion. Importantly, interindividual variation in exposure and response to rivaroxaban has been reported. Using cell-based and animal models, we demonstrated that rivaroxaban is a dual substrate of the efflux transporters MDR1 and BCRP, which played a synergistic role in modulating rivaroxaban clearance and brain accumulation. The contribution of interindividual variation in transport and metabolism to the efficacy of rivaroxaban as well as other NOACs requires to be addressed in patients.

Clopidogrel has been the gold standard antiplatelet for prevention of acute coronary syndromes and stent thrombosis following percutaneous coronary intervention. Two enzymes, CYP2C19 and PON1, have been proposed to affect clopidogrel bioactivation and efficacy. We showed that CYP2C19 but not PON1 is capable of bioactivating clopidogrel to its active metabolite. This is in line our finding that CYP2C19 genetic variation is a predictor of clopidogrel pharmacokinetics and antiplatelet response while PON1 is not.

Taken together, these studies demonstrate the contribution of SNPs to the variation in efficacy and toxicity of cardiovascular drugs, enabling personalized medicine for patients, where an individual’s genetic makeup is used to guide drug selection and dosing.

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