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Therapeutic Lessons from Pharmacogenetics

Elliot S. Vesell, MD, ScD
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Pennsylvania State University College of Medicine Hershey, PA 17033-0850 Requests for Reprints: Elliot S. Vesell, MD, ScD, Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033-0850. Requests for Reprints: Elliot S. Vesell, MD, ScD, Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033-0850.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;126(8):653-655. doi:10.7326/0003-4819-126-8-199704150-00012
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Like many other drugs, mercaptopurine and azathioprine are associated with low therapeutic indices; large interindividual variations in their metabolism; and pharmacokinetic perturbation by numerous host factors, including genetic variation. Pharmacogenetics is the exploration of genetically determined alterations in a drug's usual metabolic pathway. Such alterations are often associated with the accumulation and toxicity of a drug and with shifts to different pathways that have toxic intermediates. The paper in this issue by Yates and colleagues [1] on the molecular diagnosis of thiopurine S-methyltransferase (TPM) deficiency as a genetic basis for mercaptopurine and azathioprine toxicity provides an opportunity to discuss several therapeutic lessons from pharmacogenetics. These lessons can be condensed into the principle that large variations among patients in drug metabolism caused by multiple genetic and environmental factors require individualization of the dosage of many drugs to avoid either toxicity or undertreatment and to optimize therapy.

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