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Pharmacogenetics

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Definition

Pharmacogenetics is the study of how the actions of and reactions to drugs vary with the patient's genes.

Description

Genes are the portions of chromosomes that determine many of the traits in every living thing. In humans, genes influence race, hair and eye color, gender, height, weight, aspects of behavior, and even the likelihood of developing certain diseases. Although some traits are a combination of genetics and environment, researchers are still discovering new ways in which people are affected by their genes.

Pharmacogenetics is the study of how people respond to drug therapy. Although this science is still new, there have been many useful discoveries. It has long been known that genes influence the risk of developing certain diseases, or that genes could determine traits such as hair and eye color. Genes can also alter the risk of developing different diseases. It has long been known that people of African descent were more likely to have sickle cell anemia than people of other races. People of Armenian, Arab, and Turkish heritage are more prone to familiar Mediterranean fever than people of other nationalities. More recently, discoveries have shown that genes can determine other aspects of each individual, down to the level of the enzymes produced in the liver. Since these enzymes determine how quickly a drug is removed from the body, they can make major differences in the way people respond to drugs. Some of the most basic work concerns the way race and gender influence drug reactions—and race and gender are genetically determined.

Women often respond differently than men to drugs at the same dose levels. For example, women are more likely to have a good response to the antidepressant drugs that act as serotonin specific reuptake inhibitors (SSRIs, the group that includes Prozac and Paxil) than they are to the older group of tricyclic antidepressants (the group that includes Elavil and Tofranil). Women have a greater response to some narcotic pain reliving drugs than do men, but get less relief from some non-narcotic pain medications. Women may show a greater response to some steroid hormones than men do, but have a lower level of response to some anti-anxiety medications than men.

Race may also affect the way people respond to some medications. In this case, race implies specific genetic factors that are generally, but not always, found among members of specific ethnic groups. For example, the angiotensin II inhibitor enalopril (Vasotec), which is used to lower blood pressure, works better in Caucasians than in Blacks. Carvedilol (Coreg), a beta-adrenergic blocking agent that is also used to lower blood pressure, is more effective than other drugs in the same class when used to treat Black patients. Black patients with heart failure appear to respond better to a combination of hydralazine and isosor-bide than do Caucasian patients using the same medication.

More specific research has identified individual genes than may influence drugs response, without relying on group information such as gender and race. Specific genes have been identified that may determine how patients will respond to specific drugs. For example, some genes may determine whether people will get pain relief from codeine, or how well they will respond to drugs used to treat cancer.

— Sam Uretsky



 
 
Dictionary: phar·ma·co·ge·net·ics  (fär'mə-kō-jə-nĕt'ĭks) pronunciation
n. (used with a sing. verb)

The study of genetic factors that influence an organism's reaction to a drug.

pharmacogenetic phar'ma·co·ge·net'ic adj.
 
Medical Dictionary: phar·ma·co·ge·net·ics
(fär'mə-kō-jə-nĕt'ĭks)
n.

The study of genetic factors that influence an organism's reaction to a drug.

 
Veterinary Dictionary: pharmacogenetics

The study of the relationship between genetic factors and the nature of responses to drugs.

  • multifactorial p. — the metabolism of many drugs is determined by the action of an unknown number of genes, besides an unknown number of non-genetic effects; as a result a continuous distribution of drug concentrations in patients, ranging from subtherapeutic to toxic, may ensue.
 
Wikipedia: pharmacogenetics

The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing response to drugs, while pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. Pharmacogenetics considers one or at most a few genes of interest, while pharmacogenomics considers the entire genome.

Pharmacogenetics and adverse drug reactions

Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in, drug metabolism with a particular emphasis on improving drug safety. The wider use of pharmacogenetic testing is viewed by many as an outstanding opportunity to improve prescribing safety and efficacy. Driving this trend are the 106,000 deaths and 2.2 Million serious events caused by adverse drug reactions in the US each year (Lazarou 1998). As such ADRs are responsible for 5-7% of hospital admissions in the US and Europe, lead to the withdrawal of 4% of new medicines and cost society an amount equal to the costs of drug treatment (Ingelman-Sundberg 2005). Comparisons of the list of drugs most commonly implicated in adverse drug reactions with the list of metabolizing enzymes with known polymorphisms found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001).

History

The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500 Caucasians has less efficient variant of the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride.[citation needed] As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic).

Azathioprine, methotrexate and TPMT (thiopurine methyl transferase

One of the earliest tests for a genetic variation resulting in a clinically important consequence was on the enzyme thiopurine methyltransferase (TPMT). TPMT metabolizes 6-mercaptopurine and azathioprine, two drugs used in a range of indications, from childhood leukemia to autoimmune diseases. In people with a deficiency in TPMT, metabolism must proceed by other pathways, one of which leads to a metabolite that is toxic to the bone marrow; these people are at risk of a potentially fatal bone marrow suppression. In 85-90% of affected people, this deficiency results from one of three variant alleles. One in 300 people have two variant alleles; these people need only 6-10% of the standard dose of the drug, and, if treated with the full dose, will develop severe bone marrow suppression. For them, genotype predicts clinical outcome, a prerequisite for an effective pharmacogenetic test. Around 10% of people are heterozygous and produce a reduced quantity of functional enzyme. Overall, they are at greater risk of adverse effects, although as individuals their genotype is not necessarily predictive of their clinical outcome, which makes the interpretation of a clinical test difficult. Recent research suggests that children who are heterozygous may have a better response to treatment, which raises whether people who have two wild-type alleles could tolerate a higher therapeutic dose. The US Food and Drug Administration (FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and azathioprine. Hitherto the information has carried the warning that inherited deficiency of the enzyme could increase the risk of severe bone marrow suppression. Now it will carry the recommendation that people who develop bone marrow suppression while receiving 6-mercaptopurine or azathioprine be tested for TPMT deficiency. Variation in TPMT affects a small proportion of people, though seriously. As part of the inborn system for clearing the body of xenobiotics, the cytochrome P450 oxidases (CYP450) are heavily involved in drug metabolism, and variations in CYP450s affect large populations. One member of the CYP450 superfamily, CYP2D6, now has over 75 known allelic variations, some of which lead to no activity, and some to enhanced activity. An estimated 29% of people in parts of East Africa may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller codeine (which is activated by the enzyme).

References

  • Abbott A. With your genes? Take one of these, three times a day. Nature 2003;425:760-762.
  • Evans WE and McLeod HL. Pharmacogenomics – Drug Disposition, Drug Targets, and Side Effects. New Engl J Med 2003;348:358-349.
  • Ingelman-Sundberg M, Rodrquez-Antona C, Pharmacogenetics of drug-maetabolizing enzymes: implications for a safer and more effective drug therapy. Phil Trans R Soc B 360:1563-1570 2005
  • Lazarou, J, Pomeranz BH, Corey PN, Incidence of Adverse Drug Reactions in Hospitalized Patients: A meta-analysis of prospective studies. JAMA 1998;279:1200-1205
  • Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 2001;286:2270-2279.
  • Weinshilboum R. Inheritance and Drug Response. New Engl J Med 2003; 348:529-537.


See also

External links


Genomics topics
Genome project | Paleopolyploidy | Glycomics | Human Genome Project | Proteomics
Chemogenomics | Structural genomics | Pharmacogenetics | Pharmacogenomics | Toxicogenomics | Computational genomics
Bioinformatics | Cheminformatics | Systems biology

 
 

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Dictionary. The American Heritage® Dictionary of the English Language, Fourth Edition Copyright © 2007, 2000 by Houghton Mifflin Company. Updated in 2007. Published by Houghton Mifflin Company. All rights reserved.  Read more
Medical Dictionary. The American Heritage® Stedman's Medical Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Company Read more
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Wikipedia. This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Pharmacogenetics" Read more

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