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Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD

Nature Clinical Practice Gastroenterology & Hepatology volume 4, pages 686–694 (2007)Cite this article

Abstract

Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5′-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.

Key Points

  • The pharmacological activity of thiopurine therapy is in part mediated by the specific metabolite 6-thioguanosine 5′-triphosphate, which induces apoptosis of activated T cells

  • The complex pharmacology and metabolism of thiopurines have been partly elucidated, leading to the development of novel strategies (e.g. metabolite measurements and thiopurine S-methyltransferase determination) to optimize thiopurine therapy

  • Frequent hematological and biochemical monitoring, including complete blood counts and liver tests, remain the best-accepted methods for toxicity screening

  • The frequency of nodular regenerative hyperplasia as an adverse event during thiopurine therapy is probably underestimated—the induction of this hepatotoxic feature might be thiopurine-dose-dependent or metabolite-level dependent

  • A maintenance dosage of 6-thioguanine not exceeding 25 mg daily can be considered rescue therapy exclusively for patients with IBD who are intolerant of, or resistant to, standard therapies; 6-thioguanine should only be administered in a clinical trial setting under close (hepatotoxicity) surveillance, at least until more toxicity data are available

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Figure 1: A simplified schematic of the metabolism of thiopurines.

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Authors and Affiliations

  1. and CJJ Mulder is a Professor in Gastroenterology and Hepatology in the Department of Gastroenterology and Hepatology, and P de Graaf is a Hospital Pharmacist in the Department of Clinical Pharmacology, NKH de Boer is a Fellow in Gastroenterology and Hepatology, AA van Bodegraven is a Gastroenterologist and Head of the Inflammatory Bowel Disease section, B Jharap is a Fellow in Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.,

    Nanne KH de Boer, Adriaan A van Bodegraven, Bindia Jharap, Peer de Graaf & Chris JJ Mulder

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de Boer, N., van Bodegraven, A., Jharap, B. et al. Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Rev Gastroenterol Hepatol 4, 686–694 (2007). https://doi.org/10.1038/ncpgasthep1000

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