Pharmacogenomics--drug disposition, drug targets, and side effects.

From St. Jude Children’s Research Hospital and the University of Tennessee Colleges of Pharmacy and Medicine, Memphis (W.E.E.); and Washington University Medical School, St. Louis (H.L.M.). Address reprint requests to Dr. Evans at St. Jude Children’s Research Hospital, 332 N. Lauderdale St., Memphis, TN 381010318, or at [email protected]. t is well recognized that different patients respond in different ways to the same medication. These differences are often greater among members of a population than they are within the same person at different times (or between monozygotic twins). 1 The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response; it is estimated that genetics can account for 20 to 95 percent of variability in drug disposition and effects. 2 Although many nongenetic factors influence the effects of medications, including age, organ function, concomitant therapy, drug interactions, and the nature of the disease, there are now numerous examples of cases in which interindividual differences in drug response are due to sequence variants in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets. 3-5 Unlike other factors influencing drug response, inherited determinants generally remain stable throughout a person’s lifetime. Clinical observations of inherited differences in drug effects were first documented in the 1950s, 6-9 giving rise to the field of pharmacogenetics, and later pharmacogenomics. Although the two terms are synonymous for all practical purposes, pharmacogenomics uses genome-wide approaches to elucidate the inherited basis of differences between persons in the response to drugs. More than 1.4 million single-nucleotide polymorphisms were identified in the initial sequencing of the human genome, 10 with over 60,000 of them in the coding region of genes. Some of these single-nucleotide polymorphisms have already been associated with substantial changes in the metabolism or effects of medications, and some are now being used to predict clinical response. 3-5,11 Because most drug effects are determined by the interplay of several gene products that influence the pharmacokinetics and pharmacodynamics of medications, including inherited differences in drug targets (e.g., receptors) and drug disposition (e.g., metabolizing enzymes and transporters), polygenic determinants of drug effects (Fig. 1) have become increasingly important in pharmacogenomics. In this review, we focus on the therapeutic consequences of inherited differences in drug disposition and drug targets. An accompanying review 12