Inheritance and drug response.

From the Departments of Molecular Pharmacology and Experimental Therapeutics and Medicine, Mayo Medical School, Mayo Clinic, and Mayo Foundation, Rochester, Minn. Address reprint requests to Dr. Weinshilboum at the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School–Mayo Clinic– Mayo Foundation, Rochester, MN 55905, or at [email protected]. he promise of pharmacogenetics, the study of the role of in heritance in the individual variation in drug response, lies in its potential to identify the right drug and dose for each patient. Even though individual differences in drug response can result from the effects of age, sex, disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the likelihood of an adverse reaction. 1-3 This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation. The accompanying article by Evans and McLeod 4 expands on many of the themes introduced here. Once a drug is administered, it is absorbed and distributed to its site of action, where it interacts with targets (such as receptors and enzymes), undergoes metabolism, and is then excreted. 5,6 Each of these processes could potentially involve clinically significant genetic variation. However, pharmacogenetics originated as a result of the observation that there are clinically important inherited variations in drug metabolism. Therefore, this article — and the examples highlighted — focuses on the pharmacogenetics of drug metabolism. However, similar principles apply to clinically significant inherited variation in the transport and distribution of drugs and their interaction with their therapeutic targets. The underlying message is that inherited variations in drug effect are common and that some tests that incorporate pharmacogenetics into clinical practice are now available, with many more to follow. The concept of pharmacogenetics originated from the clinical observation that there were patients with very high or very low plasma or urinary drug concentrations, followed by the realization that the biochemical traits leading to this variation were inherited. Only later were the drug-metabolizing enzymes identified, and this discovery was followed by the identification of the genes that encoded the proteins and the DNA-sequence variation within the genes that was associated with the inherited trait. Most of the pharmacogenetic traits that were first identified were monogenic — that is, they involved only a single gene — and most were due to genetic polymorphisms; in other words, the allele or alleles responsible for the variation were relatively common. Although drug effect is a complex phenotype that depends on many factors, early and often dramatic examples involving succinylcholine and isoniazid facilitated acceptance of the fact that inheritance can have an important influence on the effect of a drug. Today there is a systematic search to identify functionally significant variations in DNA sequences in genes that influence the effects of various drugs. 4 t