Fundamentals and applications of pharmacogenetics or the clinical laboratory

Metabolism and disposition of foreign compounds, including pharmaceuticals, is dependent upon a host of factors. However, a genetic basis for individuality in drug metabolism has long been recognized and more recently has been confirmed. It is now well understood that a finite number of inherited sequence variants (alleles) of genes encoding drug-metabolizing enzymes give rise to discrete drug metabolism phenotypes. This primer in pharmacogenetics will introduce the clinical laboratorian to the mechanistic basis underlying the influence of genetics on pharmacology. We begin with an overview of pharmacology and introduce the importance of protein structure in maintaining steady-state drug concentrations. After review of fundamental concepts related to drug-metabolizing enzymes and genetics, we then give examples of how discrete genetic variations (polymorphism) alter the response (phenotype) to certain therapeutics in select individuals. We conclude with several analytical and interpretive considerations which must be considered by laboratories offering pharmacogenetic services.