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The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.
MedLine Citation:
PMID:  21311411     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.
Authors:
Sofie Haglund; Svante Vikingsson; Jan Söderman; Ulf Hindorf; Christer Grännö; Margareta Danelius; Sally Coulthard; Curt Peterson; Sven Almer
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-09
Journal Detail:
Title:  Therapeutic drug monitoring     Volume:  -     ISSN:  1536-3694     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7909660     Medline TA:  Ther Drug Monit     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
From the *Division of Gastroenterology and Hepatology, Department of Experimental and Clinical Medicine, Linköping University, Linköping; †Division of Medical Diagnostics, Laboratory Medicine, Ryhov Hospital, Jönköping; ‡Division of Drug Research, Department of Medicine and Health, Linköping University, Linköping; §Department of Gastroenterology, Lund University Hospital, Lund; ¶Department of Medicine, Ryhov Hospital, Jönköping; ∥Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden; and **Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
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