Mechanisms of Idiosyncratic ADRs

Idiosyncratic ADRs are observed in 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 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 CYP450 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.

CYP3A4 is involved in the metabolism of many drugs currently prescribed. Drugs that are substrates of CYP3A4 may competitively inhibit each other. Other drugs may inhibit or induce CYP3A4 activity without being substrates. The consequences of CYP3A4 polymorphism will depend on the intrinsic character of the drug, on the importance of the deficient metabolic pathway, and the existence of alternative metabolic pathways.