Imtiaz M. Shah
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK. G4 0NR

Abstract:

Pharmacogenomics and Personalised Medicine are rapidly evolving into important areas of research in Translational Medicine. Current research is focusing on patient genotype testing and using this genetic information to provide more effective targeting of drug therapy in clinical practice. Antithrombotic therapy is commonly used in the treatment of cardiovascular and cerebrovascular disease. There has been considerable interest in the role of pharmacogenomics in warfarin and clopidogrel metabolism, and its effect on drug therapeutic efficacy. Warfarin, an anticoagulant agent, is metabolised by the cytochrome P450 2C9 enzyme (CYP2C9) into its inactive metabolite. CYP2C9 displays genetic polymorphism between different patient populations, resulting in altered enzyme activity and warfarin metabolism. The two common allelic variants, CYP2C9*2 and CYP2C9*3 result in poor metaboliser (PM) phenotypes. CYP2C9 PMs on warfarin therapy have been shown to have an increased risk of adverse drug reactions (overcoagulation and bleeding). The FDA approved warfarin genotype testing in 2007 and further outcome data from pharmacogenetic clinical studies is awaited. Clopidogrel is an antiplatelet agent and belongs to the thienopyridine drug class. It is a prodrug, which requires activation via the CYP enzyme system. Clopidogrel metabolites produce their antiplatelet effect by inhibiting the platelet surface receptor, P2Y12. One of the important enzymes involved in the production of the active metabolite is CYP2C19. Recent clinical studies have demonstrated that CYP2C19 genetic polymorphism affects clopidogrel antiplatelet activity. Patients with the PM allele, CYP2C19*2, treated with clopidogrel have been shown to be at increased risk of recurrent cardiovascular events and coronary artery stent thrombosis. CYP2C19 enzyme inhibition by proton pump inhibitors has also been associated with reduced clopidogrel efficacy. The FDA has recently updated its label on clopidogrel CYP2C19 pharmacogenetic testing. Larger prospective clinical pharmacogenetic studies are ongoing to provide a more rigorous evidence-base for pharmacotyping of warfarin and clopidogrel treatment. Well-developed genomic services are also required before genotype testing is more widely used in clinical practice. This invited lecture will give a bench-to-bedside overview of CYP pharmacogenomics and antithrombotic therapy.