TAILIEUCHUNG - Chapter 005. Principles of Clinical Pharmacology (Part 10)

Multiple Variants Modulating Drug Effects As this discussion makes clear, for each drug with a defined mechanism of action and disposition pathways, a set of "candidate genes," in which polymorphisms may mediate variable clinical responses, can be identified. Indeed, polymorphisms in multiple genes have been associated with variability in the effect of a single drug. CYP2C9 loss-of-function variants are associated with a requirement for lower maintenance doses of the vitamin K antagonist anticoagulant warfarin. In rarer (. | Chapter 005. Principles of Clinical Pharmacology Part 10 Multiple Variants Modulating Drug Effects As this discussion makes clear for each drug with a defined mechanism of action and disposition pathways a set of candidate genes in which polymorphisms may mediate variable clinical responses can be identified. Indeed polymorphisms in multiple genes have been associated with variability in the effect of a single drug. CYP2C9 loss-of-function variants are associated with a requirement for lower maintenance doses of the vitamin K antagonist anticoagulant warfarin. In rarer 2 individuals homozygous for these variant alleles maintenance warfarin dosages may be difficult to establish and the risk of bleeding complications appears increased. In addition to CYP2C9 variants in the promoter region of VKORC1 encoding a vitamin K epoxide reductase predict warfarin dosages these promoter variants are in tight linkage disequilibrium . genotyping at one polymorphic site within this haplotype block provides reliable information on the identity of genotypes at other linked sites Chap. 62 . Thus variability in response to warfarin can be linked to both coding region polymorphisms in CYP2C9 and promoter haplotypes in the warfarin target VKORC1. As genotyping technologies improve and data sets of patients with well-documented drug responses are accumulated it is becoming possible to interrogate hundreds of polymorphisms in dozens of candidate genes. This approach has been applied to implicate linked noncoding polymorphisms in the HMG-CoA reductase gene as predicting efficacy of HMG-CoA reductase inhibitors and in variants in the gene-encoding corticotrophin-releasing hormone receptor 1 as predicting efficacy of inhaled steroids in asthma. Technologies are now evolving to interrogate hundreds of thousands of SNPs across the genome or to rapidly resequence each patient s genome. These approaches which have been applied to identify new genes modulating disease susceptibility Chap. 62 .

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