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Thiopurines in inflammatory bowel disease - The role of pharmacogenetics and therapeutic drug monitoring
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.ORCID iD: 0000-0002-2809-7591
Lund.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
2006 (English)In: Current Pharmacogenomics, ISSN 1570-1603, Vol. 4, no 4, 285-300 p.Article in journal (Refereed) Published
Abstract [en]

Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing inflammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol derivative and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complex and individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thiopurine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatase polymorphisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased interest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to identify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment. © 2006 Bentham Science Publishers Ltd.

Place, publisher, year, edition, pages
2006. Vol. 4, no 4, 285-300 p.
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-37120DOI: 10.2174/157016006778992813Local ID: 33739OAI: oai:DiVA.org:liu-37120DiVA: diva2:257969
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2013-09-03

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Lindqvist Appell, MalinAlmer, SvenPeterson, Curt

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Faculty of Health SciencesClinical PharmacologyGastroenterology and HepatologyDepartment of Endocrinology and Gastroenterology UHLDepartment of Clinical Pharmacology
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