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Pharmacogenomics
- It is the study of individual genotype and hence the phenotype in drug metabolism and drug effect.
- Genes encoding proteins involved in multiple pathways of drug metabolism, disposition and effects are different. For example, Thiopurine S methyl transferase affects metabolism of thiopurine and 6-mercaptopurine. Several polymorphs exist. But 3 alleles produce non-functional enzyme molecules such as TPMT*2, TPMT*3C and TPMT*3A. Hence heterozygous patients for these alleles need 50% reduction in the dose of 6 mercaptopurine.
- Based on CYP variant alleles, individuals have been categorized into 4 major phenotypes
- Poor metabolizers- Have 2 loss of function alleles
- Intermediate metabolizers- Deficient in 1 allele
- Extensive metabolizers- Have 2 copies of functional alleles
- Ultra-rapid metabolizers- Have 3 or more functional gene copies
- Examples include
- CYP2C9- For warfarin and phenytoin
- CYP2C19 activates clopidogrel. Hence absence of allele and allele with reduced function (Such as CYP2C19*2, CYP2C19*3), leads to clopidogrel resistance.
- For almost all the drugs, inter-individual differences are the rule, rather than exception. These differences result from interplay of many variables including genetics and environment
- Variables influencing drug response include
- Pathogenesis and severity of the underlying disease being treated.
- Drug interactions
- Patient’s age
- Sex
- Nutritional status
- Renal and liver function
- Presence of concomitant illnesses
- Other medications
- Inherited components of inter-individual differences in drug response.
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