Abstract
Pharmacogenetics and pharmacogenomics deal with the genetic basis underlying variable drug response in individual patients. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. On the other hand, pharmacogenomic studies encompass the sum of all genes, i.e., the genome. Numerous genes may play a role in drug response and toxicity, introducing a daunting level of complexity into the search for candidate genes. The high speed and specificity associated with newly emerging genomic technologies enable the search for relevant genes and their variants to include the entire genome. These new technologies have essentially spawned a new discipline, termed pharmacogenomics, which seeks to identify the variant genes affecting the response to drugs in individual patients. Moreover, pharmacogenomic analysis can identify disease susceptibility genes representing potential new drug targets. All of this will lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. Current concepts in drug therapy often attempt treatment of large patient populations as groups, irrespective of the potential for individual, genetically-based differences in drug response. In contrast, pharmacogenomics may help focus effective therapy on smaller patient subpopulations which although demonstrating the same disease phenotype are characterized by distinct genetic profiles. Whether and to what extent this individual, genetics-based approach to medicine results in improved, economically feasible therapy remain to be seen.
To exploit these opportunities in genetic medicine, novel technologies will be needed, legal and ethical questions must be clarified, health care professionals must be educated, and the public must be informed about the implications of genetic testing in drug therapy and disease management.
Similar content being viewed by others
References
Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. JAMA. 1998;279:1200–1205.
Sadee W. Finding the right drug for the right patient. Pharm Res. 1998;15:959–963.
Maynard Smith J. The Theory of Evolution. Baltimore, Maryland: Penguin Books; 1962.
Garrod AE. The incidence of alcaptonuria: a study in chemical individuality. Lancet. 1902;ii:1616–1620.
Snyder LH. Studies in human inheritance. Ohio J Sci. 1932;32:436–468.
Ford EB. Genetic Polymorphism. London: Faber & Faber; 1965.
Nebert DW. Pharmacogenetics: 65 candles on the cake. Pharmacogenetics. 1997;7:435–440.
Kalow W. Pharmacogenetics: heredity and the response to drugs. Philadelphia: W. B. Saunders; 1962.
Carsen PE, Flanagan CL, Iokes CE, Alving AS. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956;124,484–485.
Hughes HB, Biehl JP, Jones AP, Schmidt LH. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am Rev Tuberculosis. 1954;70:266–273.
Evans DAP, Manley KA, McKusick VA. Genetic control of isoniazid metabolism in man. Br Med J. 1960;2:485–490.
Vatsis K, Martell KJ, Weber WW. Proc Natl Acad Sci U S A. 1991;88:6333.
Motulsky AG. Drug reactions, enzymes and biochemical genetics. JAMA. 1957;165:835–837.
Eichelbaum M, Steincke B, Dengler JJ. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1977;16:183–187.
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651–62.
Tai H, Krynetski EY, Yates CR, et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet. 1996;58:694–702.
Goldenberg MM. Transtuzumab, a recombinant DNA derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Therapeut. 1999;21:309–318.
Baselge J, Norton L, Albanell J, Kim YM, Mendelsohn J. Recombinant humanized anti-HER2 antibody (HERCEPTIN) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xeno-grafts. Cancer Res. 1998;58:2825–2831.
Touw DJ. Clinical implications of genetic polymorphisms and drug interactions mediated by cytochrome P450 enzymes. Drug Metab Drug Interact. 1997;14:55–82.
Evans DAP. Genetic factors in drug therapy. In: Clinical and Molecular Pharmacogenetics. Cambridge: Cambridge University Press; 1993.
Buchert E, Woosley RL. Clinical implications of variable antiarrythmic drug metabolism. Pharmacogenet. 1992;2:2–11.
Dahl AK, Bertilsson, L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenet. 1993;3:61–70.
Tanaka E, Hisawa S. Clinically significant pharmacokinetic drug interactions with psychoactive drugs: antidepressents and antipsychotics and the cytochrome P450 system. J Clin Pharm Ther. 1999;24:7–16.
de Morais S, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419–15422.
Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med. 1995;73:39–553.
Gonzales FJ. Pharmacogenetic phenytyping and genotyping. Present status and future potential. Clin Pharmacokinet. 1994;26:59–70.
Ball SE, Scatina JA, Sisenwine SF, Fisher GL. The application of in vitro models of drug metabolism and toxicity in drug discovery and drug development. Drug Chem Toxicity. 1995;18:1–28.
Guengerich F. The Environmental Genome Project: Functional analysis of polymorphisms. Environment Health Perspect. 1998;106:365–368.
Kleyn PW, Vesell ES. Genetic variation as a guide to drug development. Science. 1998;281:1820–1821.
Sadee W. Pharmacogenomics. BMJ. 1999;319:1286.
Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–491.
Iyer VR, Eisen MB, Ross DT, et al. The transcriptional program in the response of human fibroblasts to serum. Science. 1999;283,83–87.
Schachter B. Pharming the Genome. Biomednet [serial online]. October 30, 1998;41.
Fluri KG, Fitzpatrick G, Chiem N, Harrison DJ. Integrated capillary electrophoresis devices with an efficient postcolumn reactor in planar quartz and glass chips. Anal Chem. 1996;68:4285–4290.
Jacobson SC, Ramsey SC. Integrated microdevice for DNA restriction fragment analysis. Anal Chem. 1996;68:720–723.
Blanchard AP, Friend SH. Cheap DNA arrays-it’s not all smoke and mirrors. Nature Biotech. 1999;17:953.
Russo E. Big pharma hedges its bets. The Scientist. 1999;13:1.
Poste G. In Bio ’98 International Meeting and Exposition 1–9. New York: RAND Corporation; 1999.
Weber WW. Pharmacogenetics. New York: Oxford University Press; 1997.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: March 7, 2000.
Rights and permissions
About this article
Cite this article
Mancinelli, L., Cronin, M. & Sadée, W. Pharmacogenomics: The promise of personalized medicine. AAPS PharmSci 2, 4 (2000). https://doi.org/10.1208/ps020104
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/ps020104