Pharmacogenetics/Pharmacogenomics of Drug-Metabolizing Enzymes and Transporters

After the completion of the Human Genome Project, the growing information on the correlation of drug pharmacokinetics (PK) and pharmacodynamics (PD) with patients' genomic makeup has allowed a better understanding of the mechanisms underlying the interindividual variability in treatment response and toxicity. Pharmacogenetics/pharmacogenomics (PGx) studies identified genetic heterogeneity of the enzymes and transporters involved in drug and xenobiotic absorption, distribution, metabolism and excretion (ADME) or immunological responses, with a multitude of gene-drug response associations. Therefore, the variability in drug response has a strong impact on dosing, drug efficacy and risk of adverse reactions, hypersensitivity reactions, drug resistance and clinical outcome. Several phase I and phase II drug metabolizing enzymes are inducible and/or polymorphic and can cause abolished, quantitatively or qualitatively impaired or enhanced biotransformation. Also, other rare mutations may have an important impact on drug response. Hence, the discovery of PGx biomarkers may lead to tailored treatment and dosing decisions for a precision medicine approach. In this article we focus on PGx advancements in ADME genes (phase I/II enzymes and transporters), other rare variants and variations in human leukocyte antigen (HLA) genes in relation to drug response. The biological consequences for susceptibility and resistance to different diseases are also discussed.