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No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease

Lindqvist, M. ; Hindorf, Ulf LU ; Almer, S. ; Soderkvist, P. ; Strom, M. ; Hjortswang, H. and Peterson, C. (2006) In Nucleosides, Nucleotides & Nucleic Acids 25(9-11). p.1033-1037
Abstract
The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naive patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were... (More)
The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naive patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35). (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inflammatory bowel, thiopurine methyltransferase, enzyme induction, TPMT gene expression, disease
in
Nucleosides, Nucleotides & Nucleic Acids
volume
25
issue
9-11
pages
1033 - 1037
publisher
Taylor & Francis
external identifiers
  • wos:000242019000013
  • scopus:33750459930
ISSN
1525-7770
DOI
10.1080/15257770600890814
language
English
LU publication?
yes
id
ff8fb2be-defa-49a0-8063-73afb8430c5b (old id 376856)
date added to LUP
2016-04-01 11:45:47
date last changed
2020-01-12 08:33:36
@article{ff8fb2be-defa-49a0-8063-73afb8430c5b,
  abstract     = {The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naive patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35).},
  author       = {Lindqvist, M. and Hindorf, Ulf and Almer, S. and Soderkvist, P. and Strom, M. and Hjortswang, H. and Peterson, C.},
  issn         = {1525-7770},
  language     = {eng},
  number       = {9-11},
  pages        = {1033--1037},
  publisher    = {Taylor & Francis},
  series       = {Nucleosides, Nucleotides & Nucleic Acids},
  title        = {No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease},
  url          = {http://dx.doi.org/10.1080/15257770600890814},
  doi          = {10.1080/15257770600890814},
  volume       = {25},
  year         = {2006},
}