Drug metabolism and variability among patients in drug response.

N Engl J Med 2005;352:2211-21. Copyright © 2005 Massachusetts Medical Society. hysicians prescribe drugs on the basis of the characteristics of the medications and on the probability that reliable and reproducible clinical effects will result. However, differences in drug response among patients are common, often leading to challenges in optimizing a dosage regimen for an individual patient. Most major drugs are effective in only 25 to 60 percent of patients, 1 and more than 2 million cases of adverse drug reactions occur annually in the United States, including 100,000 deaths. 2 Such variability in drug response among patients is multifactorial, including environmental, genetic, and disease determinants that affect the disposition (absorption, distribution, metabolism, and excretion) of a given drug. The interplay of these factors determines the profile of the plasma concentration over time for a drug and, therefore, its elicited pharmacologic effect at the site of interaction with targets (such as receptors and enzymes). Too little exposure leads to an ineffective drug regimen, and too much creates the potential for adverse effects. Recognition of such general relationships is long-standing, and information about some drugs is extensive. In contrast, the application of the information is often less than ideal. There is now, however, a general understanding of the many differences among patients in the disposition and clinical consequences of drugs, especially when cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizing enzymes, are involved in the metabolism of a drug. The characteristics of the various cytochrome P-450 enzymes are well established, and the involvement of these enzymes in the metabolism of most commonly used drugs is known. This knowledge may provide a basis for understanding and predicting individual differences in drug response, which can be caused by drug interactions and genetic variability. Drugs may be metabolized by a variety of sequential or competitive chemical processes involving oxidation, reduction, and hydrolysis (phase I reactions) or glucuronidation, sulfation, acetylation, and methylation (phase II reactions). Generally, the water solubility of the resulting metabolites is greater, thus enhancing their removal. This review will focus on cytochrome P-450 enzymes that are important in oxidative drug metabolism.