Thiopurines in Inflammatory Bowel Disease

L. J. J. Derijks; L. P. L. Gilissen; P. M. Hooymans; D. W. Hommes


Aliment Pharmacol Ther. 2006;24(5):715-729. 

In This Article

Summary and Introduction


Background: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity.
Aim: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy.
Methods: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'.
Results: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such.
Conclusions: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.


Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice, azathioprine (AZA) or mercaptopurine (MP) are not effective in one-third of patients and up to one-fifth of patients discontinues thiopurine therapy because of adverse events. Major advances in mechanistic and biochemical fields contributed to develop new strategies to improve pharmacotherapy. This review of literature focuses on thiopurine pharmacology, pharmacogenetics, interactions and new strategies for optimization of pharmacotherapy. Thiopurine efficacy and toxicity are described in less detail because it is respectively well established and generally understood.


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