Pharmacogenomics and individualized medicine.
ADME-enabling technologies for drug design and development. Zhang D, Surapaneni S, eds. Hoboken, NJ: John Wiley & Sons, Inc., 2012 Feb; :95-107
It is well established that in a large patient population, individuals may respond to the same medication differently in drug efficacy, drug safety, or both. One measurable parameter of variability in drug response is the plasma drug level that sometimes varies as much as several hundredfold among patients. Therefore, even with the best drug available, the standard daily dose that is proven to be efficacious and safe for the majority of patients may be ineffective or even harmful for a small number of patients. Although numerous factors can influence the outcome of a drug treatment in individual patients, it is generally accepted that genetic variations in humans play a major role in determining the variability of disease phenotypes, drug efficacy, and drug side effect (Lu, 1998; Meyer, 2000; Evans and McLeod, 2003; Weinshilboum, 2003a; Evans and Reiling, 2004; Eichelbaum et aI., 2006; Lin, 2007). The human genome sequence provides a special record of human evolution. This sequence varies among populations and individuals. As the complete sequence of the human genome became available, the impact of the variability of the human genome on the pathogenesis of important diseases and the responses to drug therapy in humans can be readily analyzed. Parallel to the rapid accumulation of the knowledge on the genome-disease and genome-drug interactions, there arises a high hope that individualized medicine will soon become a reality. In this chapter, we will examine the origins of individual variability in drug treatment; the role of drug targets, drug metabolizing enzymes, and drug transporters in determining the individual variability in drug therapy; and the many challenges we face in reaching the goal of individualized medicine.
Drugs; Drug-interaction; Drug-therapy; Pharmacodynamics; Pharmacology; Genes; Genetic-factors; Genetics; Medical-care; Medical-treatment; Metabolism; Biological-effects; Biological-transport; Diseases; Safety-measures; Regulations; Medicinal-chemicals; Pathogenesis; Metabolic-activation; Enzyme-activity; Enzymes; Cell-damage; Humans; Physiological-factors; Gene-mutation; DNA-damage; Deoxyribonucleic-acids; Amino-acids; Morphology
Q. Ma, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV, 26505, USA
ADME-enabling technologies for drug design and development