Importance of Pharmacogenetics to Variability in Drug Response

An individual's response to a given drug depends on a complex interplay among many environmental and genetic factors (Figure 4-1). Genetic factors account for most of the variation in metabolic rates for many drugs. Heritability can account for 75-85% of the variability in pharmacokinetic half-lives for drugs that are eliminated by metabolism. Cytotoxicity of drugs also appears to be heritable.

Several genetic polymorphisms of drug-metabolizing enzymes result in monogenic traits in which genotype predicts phenotype. In retrospective analyses, half of adverse drug reactions were associated with drugs that are substrates for polymorphic drug-metabolizing enzymes. Thus, drugs metabolized by enzymes that exhibit polymorphic activity, which make up only 22% of all drugs, disproportionately account for adverse drug reactions. Prospective genotype determinations of these enzymes may allow us to avoid many adverse drug reactions.

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