May 2001 • Volume 7 • Number 5
Pharmacogenetics should help clinicians individualize drug therapies
BY DENNIS CONNAUGHTON
P harmacogenetics promises this: Using what scientists know from the Human Genome Project, clinicians should be able to tailor drug therapy to the individual, based on the individual's genetic makeup, to avoid drug toxicity and maximize therapeutic benefits.
However, according to speakers at the annual meeting of the American Academy of Allergy, Asthma and Immunology here in March, that promise may take five years or more to become reality.
"Pharmacogenetics is going to be one of the very important applications of the Human Genome Project," said Jeffrey Drazen, M.D., editor-in-chief of the New England Journal of Medicine and a professor of medicine at Harvard University in Cambridge, Mass. "Pharmacogenetics is defined as the use of genetic information to ascertain who will respond favorably or unfavorably to a given type of treatment."
The way an individual metabolizes drugs is based on his or her phenotype, Drazen said. The result: different outcomes in different individuals treated under the same therapeutic regimen. "The idea is that some people may be undertreated or overtreated, given their genetic makeup," he said.
Drazen predicted that within five years, clinicians will be able to order a drug-response phenotype profile for an individual, just as they order a complete blood count today. That profile will help physicians individualize drug therapies.
Another speaker on pharmacogenetics was Richard Weinshilboum, M.D., professor of molecular pharmacology and experimental therapeutics and medicine at Mayo Clinic in Rochester, Minn. He described studies of immunosuppressive drugs, such as the anti-leukemia drug 6-mercaptopurine, that show differences in drug metabolism associated with individual phenotypes.
"Most people metabolize 6-mercaptopurine quickly, and so their dosage must be high enough to treat leukemia and prevent relapses," Weinshilboum said. "Others metabolize the drug slowly and need lower doses to avoid toxic side effects. A small portion of people metabolize the drug so poorly that its effects can be fatal. This diversity in responses is due to variations in the gene for an enzyme called TPMT, or thiopurine methyltransferase."
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Elliot Israel, M.D., acting chief of the pulmonary division at Brigham and Women's Hospital in Boston, discussed a study he and others did. They examined the effects of genetics on how asthmatic patients respond to regular use of albuterol.
Inhaled beta2-agonists are the most commonly prescribed asthma medications in the world, Israel said. Controversy exists over whether regular use of beta-agonists has a deleterious effect on the control of asthma. Israel's study found that asthmatics with a homozygous arginine genotype at position 16 of the beta2-adrenergic receptor had a decline in airway function with regular use of a beta-agonist.
"If corroborated, our findings suggest that these individuals may benefit by avoiding regularly scheduled beta-agonists and might be candidates for earlier intervention with anti-inflammatory agents," Israel said.
Lanny Rosenwasser, M.D., head of the allergy department at the National Jewish Medical and Research Center in Denver, has reviewed studies of how genetics may affect resistance to steroid medications among asthmatics. He concluded that the task of applying genetic research to clinical treatment may be a daunting one.
Rosenwasser said there are some four million small variations, known as single nucleotide polymorphisms (SNPs), in genetic sequences. "SNP biology is becoming the major driving force for understanding the genetic variations seen in complex disease states such as asthma," he said. "Interventions related to SNP biology and variations in SNP biology will probably have the greatest clinical impact in the future."
FP Report is published by the AAFP News Department.
Copyright © 2001 by American Academy of Family Physicians.
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