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 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. 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.

Pharmacogenetics and adverse drug reactions

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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. 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).

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 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.

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Pharmacogenetics and ADHD by Mark A Stein, Department of Psychiatry, University of Illinois at Chicago http://ow.ly/SWel
VeoMed (VeoMed Team) Tue, 05 Jan 2010 16:38:14 -0000
Pharmacogenetics and ADHD by Mark A Stein, Department of Psychiatry, University of Illinois at Chicago http://ow.ly/SWel

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