Review article: thiopurines in inflammatory bowel disease.
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.


OBJECTIVE
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.
Derijks
L J J
LJ
Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands. l.derijks@mmc.nl
Gilissen
L P L
LP
Hooymans
P M
PM
Hommes
D W
DW
D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013866:Thioguanine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D014969:Xanthine Oxidase / Q000378:metabolism
D005765:Gastrointestinal Agents; D011687:Purines; D015122:Mercaptopurine; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine