Review Article

European Journal of Clinical Pharmacology

, Volume 64, Issue 8, pp 753-767

First online:

Clinical pharmacology and pharmacogenetics of thiopurines

  • Srikumar SahasranamanAffiliated withDrug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation
  • , Danny HowardAffiliated withDrug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation
  • , Sandip RoyAffiliated withDrug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation Email author 

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The thiopurine drugs—azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine—are widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease, and solid organ transplant rejection. However, thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life-threatening toxicity, most often myelosuppression. Thiopurine S-methyltransferase (TPMT; EC, an enzyme that catalyzes S-methylation of these drugs, exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity after receiving standard doses of thiopurine medications. This report reviews the recent advances in the knowledge of the mechanism of action as well as the molecular basis and interethnic variations of TPMT and inosine triphosphate pyrophosphatase (ITPase; EC, another enzyme implicated in thiopurine toxicity. In addition, an update on pharmacokinetics, metabolism, drug-drug interactions, safety, and tolerability of thiopurine drugs is provided.


Thiopurine Thiopurine methyltransferase Inosine triphosphate pyrophosphate Polymorphism Pharmacokinetics Drug interactions