Mechanisms of Idiosyncratic ADRs

Idiosyncratic ADRs are unpredictable and affect a small number of patients. Factors influencing drug response phenotype include age, gender, underlying disease, and genetic and epigenetic mechanisms.^1,4,5 Genetic polymorphism and epigenetic factors (i.e., heritable changes in gene function and expression not related to DNA sequencing) influence the outcome of pharmacotherapy and have been implicated in both pharmacokinetic and pharmacodynamic variations.

Inherited variations in enzymes that catalyze drug metabolism are the most common causes of variation in response to medications. The effects of genetic polymorphism on drug metabolism are the most prominent with five isoforms of the cytochrome P450 enzymes, i.e., CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Isoenzyme-induced variations in drug metabolism may lead to significant differences in the efficacy and toxicity of drugs.