Clinical pharmacology and pharmacogenetics of thiopurines.

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Sahasranaman S, Howard D, Roy S

Clinical pharmacology and pharmacogenetics of thiopurines.

Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28.

PubMed ID

18506437 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Mercaptopurine	Amidophosphoribosyltransferase	Protein	Humans	Unknown	Inhibitor	Details
Mercaptopurine	Inosine-5'-monophosphate dehydrogenase (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details
Tioguanine	DNA	Nucleotide	Humans	Yes	Intercalation	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Azathioprine	Thiopurine S-methyltransferase	Protein	Humans	Unknown	Substrate	Details