Pharmacogenetics

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 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 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 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 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

• Genomics
  • Chemogenomics
  • Structural genomics
  • Pharmacogenomics
  • Toxicogenomics