Health care providers and patients have long recognized that people often respond differently to the same medicine, both in terms of efficacy and "side effects,'' or adverse drug reactions (ADRs). There are many factors that contribute to this inter-individual variability in response to medications, including: the pathogenesis and severity of the disease being treated; concomitant medications and drug interactions; and the patient's age, renal and liver function, concomitant illnesses, nutrition and lifestyle (smoking, alcohol use, weight, fitness) (Meyer, 2000). Genetic factors that affect the kinetics and dynamics of drugs play an even greater role in determining an individual's risk of non-response or toxicity (Evans and Relling, 1999). Although it is difficult to define the relative contribution of genetic and environmental effects in an individual, it is clear that variation in genes coding for drug-metabolizing enzymes, drug transporters, and drug receptors and targets accounts for a significant portion of the observed heterogeneity in drug response across populations.
The study of ADRs has been hampered by the use of ambiguous and inconsistent terminology and reporting. Edwards and Aronson (2000) recently proposed the following definition of an adverse drug reaction: "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, alteration of the dosage regimen, or withdrawal of the product''. ADRs may result from health care provider, pharmacy or patient error or from a variety of genetic and environmental factors. Although definitions and figures vary, it is clear that ADRs are a significant cause of morbidity, mortality and health care expense. Lazarou et al. (1998) performed a meta-analysis of 39 prospective studies from US hospitals and found that 6.7% of inpatients have a serious ADR while hospitalized, resulting in -106 000 deaths per year. White et al. (1999) estimates that hospitalizations due to ADRs in the United States cost between $30 billion and $150 billion per year, and Destenaves and Thomas (2000) report that ADRs are a major cause of non-compliance and treatment failure, especially for patients with chronic diseases. If lack of efficacy ("unexpected failure of therapy'') is included in the definition of ADRs, as suggested by Edwards and Aronson (2000), then their deleterious human and financial cost becomes even greater.
The number, severity and cost of ADRs is now recognized as a significant public health issue and has triggered interest in discovering what causes them and if and how their occurrence can be predicted and prevented. In this chapter, we will focus on the current state of knowledge regarding the genetic basis of ADRs and the important role that pharmacogenetics will play in meeting the ultimate goal of providing safer, more effective medicines.
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