European Journal of Clinical Pharmacology

, Volume 64, Issue 8, pp 753–767 | Cite as

Clinical pharmacology and pharmacogenetics of thiopurines

Review Article

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.

Keywords

Thiopurine Thiopurine methyltransferase Inosine triphosphate pyrophosphate Polymorphism Pharmacokinetics Drug interactions 

Abbreviations

6-GTP

6-Guanosine triphosphate

6-MMP or 6-MeMP

6-Methylmercaptopurine

6-MP

6-Mercaptopurine, an immunomodulator

6-TG

6-Thioguanine, the active AZA antimetabolite

6-TGN

6-Thioguanine nucleotide

6-TU

6-Thiouric acid

AZA

Azathioprine, prodrug derivative of 6-MP

CBC

Complete blood count

HPRT

Hypoxanthine phosphoribosyl transferase, an enzyme

IBD

Inflammatory bowel disease

IMPDH

Inosine monophosphate dehydrogenase

ITPase

Inosine triphosphate pyrophosphatase

MCV

Mean corpuscular volume

RBC

Red blood cell

TIMP

Thioinosic monophosphate, active metabolite

TPMT

Thiopurine methyltransferase

WBC

White blood cell

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Srikumar Sahasranaman
    • 1
  • Danny Howard
    • 1
  • Sandip Roy
    • 1
  1. 1.Drug Metabolism and PharmacokineticsNovartis Pharmaceuticals CorporationEast HanoverUSA

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