Why good drugs aren't all good

Some 100,000 deaths in the United States each year are due to adverse drug reactions and these deaths are the tip of an adverse drug reaction iceberg of some 2 million cases. In the realm of drug efficacy, most major drugs are effective in only 25 to 60 percent of patients. These statistics are the public health face of the biology of variability in drug response. Environmental, genetic, and disease factors have important roles in the absorption, distribution, metabolism, and excretion of a given drug and, consequently, these factors have important roles in the safety and efficacy outcomes for patients taking a given drug. [Continue]

The relationship between drinking one 8-oz (250-ml) glass of grapefruit juice, the CYP3A enzymes, and drugs metabolized by CYP3A such as felodipine or cyclosporine, demonstrates the multifactorial nature of response to drugs. As discussed by Grant Wilkinson in a recent issue of the New England Journal of Medicine, grapefruit juice can cause inhibition of CYP3A enzymes. With CYP3A activity inhibited, circulating levels of felodipine, for instance, increase with manifold pharmacodynamic effects and potential health consequences for the patient. For CYP3A, multiple genes play a role. For other enzymes, variability in patient response is often attributable to variablity in a single gene. The cure rate for Helicobacter pylori infection when treatment is with omeprazole and amoxicillin is 28.6 percent in patients homozygous for the "EM" (extensive metabolism) genotype and 100 percent in those homozygous for the "PM" (poor metabolism) genotype. Despite the predictive value of genotype for outcome in many treatments, the assessment of genotype is rarely done in clinical practice. Instead of genotyping, clinical practitioners moniter clinical markers. There have not yet been prospective clinical trials showing that knowledge of a patient’s genotypic profile before prescribing drugs either increases drug efficacy, prevents or reduces adverse drug reactions, or lowers the overall costs of therapy and associated sequelae.