Clinical studies of thiopurine metabolism in inflammatory bowel disease.

Ulf Hindorf

Clinical studies of thiopurine metabolism in inflammatory bowel disease.

Ulf Hindorf

Medicine, Lund

Research output: Thesis › Doctoral Thesis (compilation)

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 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.

Original language	English
Qualification	Doctor
Awarding Institution	Medicine, Lund
Supervisors/Advisors	Nilsson, Åke, Supervisor Almer, Sven, Supervisor, External person
Award date	2006 Feb 3
Publisher	Division of Gastroenterology, Department of Clinical Sciences, Faculty of Medicine, Lund University
ISBN (Print)	91-85481-38-6
Publication status	Published - 2006

Bibliographical note

Defence details

Date: 2006-02-03
Time: 09:00
Place: Föreläsningssal 4, Universitetssjukhuset, Lund

External reviewer(s)

Name: Colombel, Jean-Frédéric
Title: Professor
Affiliation: Service d'Hépatogastroentérologie, Hôpital Huriez, CHRU Lille, France

---

<div class="article_info">U Hindorf, C Peterson and S Almer. <span class="article_issue_date">2004</span>. <span class="article_title">Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy. Results from a large Swedish patient population.</span> <span class="journal_series_title">Ther Drug Monit</span>, <span class="journal_volume">vol 26</span> <span class="journal_pages">pp 673-678</span>.</div>
<div class="article_info">U Hindorf, E Lyrenäs, Å Nilsson and K Schmiegelow. <span class="article_issue_date">2004</span>. <span class="article_title">Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.</span> <span class="journal_series_title">Scand J Gastroenterol</span>, <span class="journal_volume">vol 39</span> <span class="journal_pages">pp 1105-1112</span>.</div>
<div class="article_info">U Hindorf, M Lindqvist, C Peterson, P Söderkvist, M Ström, H Hjortswang, A Pousette and S Almer. <span class="article_issue_date">2006</span>. <span class="article_title">Pharmacogenetics during standardized initiation of thiopurine therapy in inflammatory bowel disease.</span> <span class="journal_series_title">Gut</span>, (accepted)</div>
<div class="article_info">U Hindorf, M Lindqvist, H Hildebrand, U Fagerberg and S Almer. <span class="article_issue_date"></span>. <span class="article_title">Adverse events leading to modification of therapy in a large cohort of azathioprine-treated patients with inflammatory bowel disease.</span> (manuscript)</div>

Subject classification (UKÄ)

Other Clinical Medicine

Keywords

Gastroenterologi
Gastro-enterology
thiopurine methyltransferase
6-mercaptopurine
azathioprine
Inflammatory bowel disease
thiopurines
adverse events
methylated metabolites
thioguanine nucleotides

Cite this

@phdthesis{4d247891949e4a13974d98330c16759b,

title = "Clinical studies of thiopurine metabolism in inflammatory bowel disease.",

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 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.",

keywords = "Gastroenterologi, Gastro-enterology, thiopurine methyltransferase, 6-mercaptopurine, azathioprine, Inflammatory bowel disease, thiopurines, adverse events, methylated metabolites, thioguanine nucleotides",

author = "Ulf Hindorf",

note = "Defence details Date: 2006-02-03 Time: 09:00 Place: F{\"o}rel{\"a}sningssal 4, Universitetssjukhuset, Lund External reviewer(s) Name: Colombel, Jean-Fr{\'e}d{\'e}ric Title: Professor Affiliation: Service d'H{\'e}patogastroent{\'e}rologie, H{\^o}pital Huriez, CHRU Lille, France --- <div class={"}article_info{"}>U Hindorf, C Peterson and S Almer. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy. Results from a large Swedish patient population.</span> <span class={"}journal_series_title{"}>Ther Drug Monit</span>, <span class={"}journal_volume{"}>vol 26</span> <span class={"}journal_pages{"}>pp 673-678</span>.</div> <div class={"}article_info{"}>U Hindorf, E Lyren{\"a}s, {\AA} Nilsson and K Schmiegelow. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.</span> <span class={"}journal_series_title{"}>Scand J Gastroenterol</span>, <span class={"}journal_volume{"}>vol 39</span> <span class={"}journal_pages{"}>pp 1105-1112</span>.</div> <div class={"}article_info{"}>U Hindorf, M Lindqvist, C Peterson, P S{\"o}derkvist, M Str{\"o}m, H Hjortswang, A Pousette and S Almer. <span class={"}article_issue_date{"}>2006</span>. <span class={"}article_title{"}>Pharmacogenetics during standardized initiation of thiopurine therapy in inflammatory bowel disease.</span> <span class={"}journal_series_title{"}>Gut</span>, (accepted)</div> <div class={"}article_info{"}>U Hindorf, M Lindqvist, H Hildebrand, U Fagerberg and S Almer. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Adverse events leading to modification of therapy in a large cohort of azathioprine-treated patients with inflammatory bowel disease.</span> (manuscript)</div>",

year = "2006",

language = "English",

isbn = "91-85481-38-6",

series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",

publisher = "Division of Gastroenterology, Department of Clinical Sciences, Faculty of Medicine, Lund University",

school = "Medicine, Lund",

}

TY - THES

T1 - Clinical studies of thiopurine metabolism in inflammatory bowel disease.

AU - Hindorf, Ulf

N1 - Defence details Date: 2006-02-03 Time: 09:00 Place: Föreläsningssal 4, Universitetssjukhuset, Lund External reviewer(s) Name: Colombel, Jean-Frédéric Title: Professor Affiliation: Service d'Hépatogastroentérologie, Hôpital Huriez, CHRU Lille, France --- <div class="article_info">U Hindorf, C Peterson and S Almer. <span class="article_issue_date">2004</span>. <span class="article_title">Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy. Results from a large Swedish patient population.</span> <span class="journal_series_title">Ther Drug Monit</span>, <span class="journal_volume">vol 26</span> <span class="journal_pages">pp 673-678</span>.</div> <div class="article_info">U Hindorf, E Lyrenäs, Å Nilsson and K Schmiegelow. <span class="article_issue_date">2004</span>. <span class="article_title">Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.</span> <span class="journal_series_title">Scand J Gastroenterol</span>, <span class="journal_volume">vol 39</span> <span class="journal_pages">pp 1105-1112</span>.</div> <div class="article_info">U Hindorf, M Lindqvist, C Peterson, P Söderkvist, M Ström, H Hjortswang, A Pousette and S Almer. <span class="article_issue_date">2006</span>. <span class="article_title">Pharmacogenetics during standardized initiation of thiopurine therapy in inflammatory bowel disease.</span> <span class="journal_series_title">Gut</span>, (accepted)</div> <div class="article_info">U Hindorf, M Lindqvist, H Hildebrand, U Fagerberg and S Almer. <span class="article_issue_date"></span>. <span class="article_title">Adverse events leading to modification of therapy in a large cohort of azathioprine-treated patients with inflammatory bowel disease.</span> (manuscript)</div>

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - Gastroenterologi

KW - Gastro-enterology

KW - thiopurine methyltransferase

KW - 6-mercaptopurine

KW - azathioprine

KW - Inflammatory bowel disease

KW - thiopurines

KW - adverse events

KW - methylated metabolites

KW - thioguanine nucleotides

M3 - Doctoral Thesis (compilation)

SN - 91-85481-38-6

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Division of Gastroenterology, Department of Clinical Sciences, Faculty of Medicine, Lund University

ER -

Clinical studies of thiopurine metabolism in inflammatory bowel disease.

Abstract

Bibliographical note

Subject classification (UKÄ)

Keywords

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