title: Clinical pharmacology and pharmacogenetics of thiopurines.
abstract: 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 2.1.1.67), 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 3.6.1.19), another enzyme implicated in thiopurine toxicity. In addition, an update on pharmacokinetics, metabolism, drug-drug interactions, safety, and tolerability of thiopurine drugs is provided.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.
authors.forename: Srikumar
authors.initials: S
authors.lastname: Sahasranaman
authors.forename: Danny
authors.initials: D
authors.lastname: Howard
authors.forename: Sandip
authors.initials: S
authors.lastname: Roy
mesh_terms: D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D013866:Thioguanine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D044465:White People / Q000235:genetics; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; D013866:Thioguanine; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase