Therapeutic Lessons from Pharmacogenetics

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.

Pharmacogenetics encompasses almost 100 diverse monogenically transmitted conditions, including polymorphisms of N-acetyltransferase, serum butyrylcholinesterase (pseudocholinesterase), serum arylesterase (paraoxonase), glutathione S-transferase, debrisoquine, and mephenytoin [2, 3]. Drug accumulation generally arises from an abnormal enzyme that blocks the drug's usual pathway of inactivation. The parent drug is sometimes inactive, as in debrisoquine polymorphism, in which affected patients do not obtain adequate analgesia with codeine because they cannot convert it to morphine.

Many drugs participate in some pharmacogenetic conditions. For example, 30 different drugs act, to some extent, as substrates in the debrisoquine polymorphism caused by mutations of the cytochrome P450 isozyme designated CYP2D6. Generally, more than half of the total metabolism of a drug must pass through this aberrant isozyme for …