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Clinical pharmacology and pharmacogenetics of thiopurines

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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.

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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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    Srikumar Sahasranaman, Danny Howard & Sandip Roy

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Sahasranaman, S., Howard, D. & Roy, S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 64, 753–767 (2008). https://doi.org/10.1007/s00228-008-0478-6

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