Thiopurines in Inflammatory Bowel Disease

Summary and Introduction

Summary

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.

Introduction

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.

Cite this: Thiopurines in Inflammatory Bowel Disease - Medscape - Sep 01, 2006.

Table 1. Possible Utilization of Metabolite Measurement in Inflammatory Bowel Disease Patients Treated With Azathioprine or 6-mercaptopurine
Explanation	6-TGN level (in pmol/8 × 10⁸ RBC)	6-MMPR level (in pmol/8 × 10⁸ RBC)	6-MMPR/6-TGN ratio
Therapeutic target achieved	250–500	<5700	5–25
Non-compliance	<<250	<<5700	5–25
Under-dosing	<250	<5700	5–25
Potential myelotoxicity(absent TPMT activity)	>>500	<<5700	0
Possible myelotoxicity(low TPMT activity)	>500	<5700	0
Possible hepatotoxicity(high TPMT activity)	<250–500	>5700	30–100
Potential myelotoxicity(very high TPMT activity)	<<250	>>5700	>>100

6-TGN, 6-thioguaninenucleotides; 6-MMPR, 6-methylmercaptopurine ribonucleotides; pmol, picomoles; RBC, red blood cell; TPMT, thiopurine S-methyl transferase.

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Thiopurines in Inflammatory Bowel Disease

Summary and Introduction

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