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Clinical studies of thiopurine metabolism in inflammatory bowel disease.

Hindorf, Ulf LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series 2006:11.
Abstract
Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterised by a chronic or relapsing inflammation of the digestive tract. The thiopurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA, an imidazol derivative and pro-drug of 6-MP) are currently used to an increased extent in IBD, particularly in Crohn's disease.



Metabolism of thiopurines is complex and individually variable. Thus, the formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably. Thiopurine methyltrasferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for an inactive enzyme when... (More)
Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterised by a chronic or relapsing inflammation of the digestive tract. The thiopurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA, an imidazol derivative and pro-drug of 6-MP) are currently used to an increased extent in IBD, particularly in Crohn's disease.



Metabolism of thiopurines is complex and individually variable. Thus, the formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably. Thiopurine methyltrasferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for an inactive enzyme when occurring in the homozygous form. Postulating that pharmacological monitoring and TPMT determinations may improve clinical efficacy and reduce side effects of thiopurine therapy we examined TMPT variation and metabolite levels in relation to clinical findings in patients with IBD.



TPMT status was of clinical importance in the toxicity observed during thiopurine therapy. Patients with decreased TPMT activity were more prone to develop adverse events and less likely to tolerate a standard thiopurine dose due to toxicity. The formation of metabolites after dose escalation was influenced by TPMT status. Subjects with normal TPMT activity shifted the metabolism towards production of methylated metabolites, while subjects with intermediate TPMT activity exhibit pronounced elevations of TGN metabolites even with small dose escalations. There was no general induction of TPMT activity after standardized initiation of thiopurine therapy. We found no correlation between AZA dose and TGN levels in two independent patient populations, but there was a linear relationship between AZA dose and methylated metabolites. The level of TGN metabolites were related to disease activity, with higher levels in disease remission. It is thus clinically useful to monitor TGN metabolites as an evaluation of treatment intensity. The total number of adverse events was higher in patients both with high TGN and high meTIMP metabolite concentrations and high levels of methylated metabolites (meTIMP) were associated with the development of myelotoxicity.



In conclusion, these results suggest that TPMT activity measurements and pharmacological monitoring of thiopurine metabolites are useful in the clinical setting. (Less)
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author
supervisor
opponent
  • Professor Colombel, Jean-Frédéric, Service d'Hépatogastroentérologie, Hôpital Huriez, CHRU Lille, France
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Gastroenterologi, Gastro-enterology, thiopurine methyltransferase, 6-mercaptopurine, azathioprine, Inflammatory bowel disease, thiopurines, adverse events, methylated metabolites, thioguanine nucleotides
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2006:11
pages
73 pages
publisher
Division of Gastroenterology, Department of Clinical Sciences, Faculty of Medicine, Lund University
defense location
Föreläsningssal 4, Universitetssjukhuset, Lund
defense date
2006-02-03 09:00:00
ISSN
1652-8220
ISBN
91-85481-38-6
language
English
LU publication?
yes
additional info
U Hindorf, C Peterson and S Almer. 2004. Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy. Results from a large Swedish patient population. Ther Drug Monit, vol 26 pp 673-678.
U Hindorf, E Lyrenäs, Å Nilsson and K Schmiegelow. 2004. Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease. Scand J Gastroenterol, vol 39 pp 1105-1112.
U Hindorf, M Lindqvist, C Peterson, P Söderkvist, M Ström, H Hjortswang, A Pousette and S Almer. 2006. Pharmacogenetics during standardized initiation of thiopurine therapy in inflammatory bowel disease. Gut, (accepted)
U Hindorf, M Lindqvist, H Hildebrand, U Fagerberg and S Almer. . Adverse events leading to modification of therapy in a large cohort of azathioprine-treated patients with inflammatory bowel disease. (manuscript)
id
4d247891-949e-4a13-974d-98330c16759b (old id 546328)
date added to LUP
2016-04-01 16:36:47
date last changed
2019-05-21 22:13:50
@phdthesis{4d247891-949e-4a13-974d-98330c16759b,
  abstract     = {{Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterised by a chronic or relapsing inflammation of the digestive tract. The thiopurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA, an imidazol derivative and pro-drug of 6-MP) are currently used to an increased extent in IBD, particularly in Crohn's disease.<br/><br>
<br/><br>
Metabolism of thiopurines is complex and individually variable. Thus, the formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably. Thiopurine methyltrasferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for an inactive enzyme when occurring in the homozygous form. Postulating that pharmacological monitoring and TPMT determinations may improve clinical efficacy and reduce side effects of thiopurine therapy we examined TMPT variation and metabolite levels in relation to clinical findings in patients with IBD.<br/><br>
<br/><br>
TPMT status was of clinical importance in the toxicity observed during thiopurine therapy. Patients with decreased TPMT activity were more prone to develop adverse events and less likely to tolerate a standard thiopurine dose due to toxicity. The formation of metabolites after dose escalation was influenced by TPMT status. Subjects with normal TPMT activity shifted the metabolism towards production of methylated metabolites, while subjects with intermediate TPMT activity exhibit pronounced elevations of TGN metabolites even with small dose escalations. There was no general induction of TPMT activity after standardized initiation of thiopurine therapy. We found no correlation between AZA dose and TGN levels in two independent patient populations, but there was a linear relationship between AZA dose and methylated metabolites. The level of TGN metabolites were related to disease activity, with higher levels in disease remission. It is thus clinically useful to monitor TGN metabolites as an evaluation of treatment intensity. The total number of adverse events was higher in patients both with high TGN and high meTIMP metabolite concentrations and high levels of methylated metabolites (meTIMP) were associated with the development of myelotoxicity.<br/><br>
<br/><br>
In conclusion, these results suggest that TPMT activity measurements and pharmacological monitoring of thiopurine metabolites are useful in the clinical setting.}},
  author       = {{Hindorf, Ulf}},
  isbn         = {{91-85481-38-6}},
  issn         = {{1652-8220}},
  keywords     = {{Gastroenterologi; Gastro-enterology; thiopurine methyltransferase; 6-mercaptopurine; azathioprine; Inflammatory bowel disease; thiopurines; adverse events; methylated metabolites; thioguanine nucleotides}},
  language     = {{eng}},
  publisher    = {{Division of Gastroenterology, Department of Clinical Sciences, Faculty of Medicine, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Clinical studies of thiopurine metabolism in inflammatory bowel disease.}},
  volume       = {{2006:11}},
  year         = {{2006}},
}