The reality of pharmacogenomics: optimizing therapeutic decision making.

is now well established that significant interindividual variability exists in the disposition and pharmacologic effects of certain medications. Influences such as environmental exposures, nutritional status, co-morbidities, severity of disease, and concomitant medications have all been associated with heterogeneity in drug responses. In addition, the profound contribution of genetics has been appreciated for some time and is receiving greater emphasis in recent years. Approximately 1.8 million single nucleotide polymorphisms (SNPs) in the human genome have been identified by The SNP Consortium (http://snp.cshl.org), a collaboration of several companies and institutions. Numerous SNPs in genes encoding various drug-metabolizing enzymes, drug transporters, and drug targets (e.g., receptors, enzymes involved in metabolism of endogenous substrates, etc.) have been shown to be associated with interindi-vidual differences in the pharmacokinetics and pharmacodynamics of certain medications (Evans and McLeod 2003). Many in vitro and in vivo " pharmacogenetic " studies performed to date have evaluated the association between SNPs in a single gene and a specific drug's pharmacologic properties. Preclinical and clinical investigations have evaluated genetic determinants of drug metabolism and demonstrated that polymorphisms in genes encoding drug-metabo-lizing enzymes can markedly influence a drug's pharmacokinetics, change its efficacy and/or toxicity profile, and necessitate dosing changes in certain individuals. More recent studies have begun to evaluate the association between drug target polymorphisms and pharmacodynamic effects. Three well-documented " pharmacoge-netic " examples are outlined in Table 1. Because of the complex interplay between the pharmacologic effects of drugs and disease pathophysiology, inherited differences in drug responses are most likely polygenic rather than monogenic in nature (Evans and McLeod 2003). Hence, " pharmacogenomics " has emerged as a new field of study that attempts to identify and elucidate the contribution of multiple interrelated genes to the efficacy and toxicity of certain medications. Ultimately, the goal of pharma-cogenomics is to account for and minimize interindividual variability in drug response, thus allowing clinicians to enhance the efficacy and minimize the toxicities associated with drug therapy. By considering the role of multiple genes, the field of pharmacogenomics seeks to divide a given patient population into smaller, less variable, more predictable subgroups, which enables clini-cians to individualize drug therapy (i.e., to administer the right drug, at the right dose, to the right patient) (Roses 2000). For example, it is now recognized that SNPs can affect the activity of drug transporters and drug-metabolizing enzymes and can substantially influence an individual's systemic exposure to certain agents. Genetic …