Clinically relevant genetic variations in drug metabolizing enzymes

Abstract

In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.

Fig. (1)

(a) Relative abundance of drug metabolizing enzymes in human liver microsomes, “other” includes non-P450 phase I enzymes and phase II enzymes [39]. Other includes minor phase I drug metabolizing enzymes as well as phase II enzymes. (b) Percentage of prescription drugs metabolized by each P450 enzyme [39].