Journal of Crohn's and Colitis (2014) 8, 1743–1744
Available online at www.sciencedirect.com
ScienceDirect
LETTER TO THE EDITOR
Beneficial pharmacological
interaction between thiopurine
and mesalazine — Never change a
winning team
Dear Sir,
There is a well-known pharmacological interaction between mesalazines and thiopurines, leading to an increase of
the active thiopurine metabolites 6-thioguaninenucleotides
(6-TGN). This metabolite exerts its immunosuppressive potential by inducing apoptosis of activated T-lymphocytes.
Pharmacological studies have demonstrated that there is a
dose-dependent increase in 6-TGN formation during mesalazine
co-administration.1 However studies on the efficacy of this
potential beneficial drug–drug interaction are lacking. Our
letter underlines the importance of this pharmacological effect
in daily clinical IBD practice, illustrated by an interesting case.
A 44-year-old woman with left-sided ulcerative colitis
presented with a flare of bloody diarrhea, abdominal pain and
slight weight loss. Six months ago induction with prednisone and
subsequent weight-based mercaptopurine maintenance therapy was initiated. A few months before clinical deterioration,
the mesalazine dosage was lowered on the patients' request
from 4 to 2 g daily. The fecal calprotectine level was somewhat
elevated (189 μg/g feces) and sigmoidoscopy depicted a severe
left-sided colitis. Thiopurine metabolite levels demonstrated a
skewed metabolism (a so-called ultramethylation profile), with
elevated 6-methylmercaptopurine levels (6-MMP) and relatively low 6-TGN levels (Table 1). Notably, these metabolites were
within the preferred ranges 3 months before. After mesalazine
Table 1
dose escalation to again 4 g daily in adjacent to topical
induction therapy with beclomethason/mesalazine enemas,
clinical remission was achieved within 6 weeks. Thiopurine
metabolites returned to their earlier normal values (Table 1).
In general, approximately 50% discontinues thiopurines in
consequence of adverse events and refractory disease.2 An
important alleged determinant is the inter-individually determined variation in thiopurine metabolism, ultimately leading to
the generation of the key end-metabolites 6-TGN and 6-MMP.
The 6-MMP metabolites are assumed to be associated with side
effects and lack of response, and 6-TGN levels with effectiveness.3 Therapeutic drug monitoring is of importance in evaluating patients with adverse events, refractory disease or
steroid-dependency as metabolite-guided treatment leads to
an increased remission rate.4 Our case illustrates that the
addition of mesalazine alongside thiopurine therapy may well be
an attractive strategy to optimize thiopurine metabolism (as it
leads to higher 6-TGN levels) in case of therapeutic inefficacy.1
Pending large randomized studies to firmly establish
whether this proposed strategy results in clinical improvement, physicians should be aware of the synergistic effect
of mesalazines and thiopurines.
Conflict of interest
The authors declare that they have no competing interests.
Acknowledgments
None.
Dose-dependent alteration of thiopurine metabolism by mesalazine.
Prescribed drugs/time frame
8
6-TGN (pmol/8 × 10 )
6-MMPR (pmol/8 × 108)
Mesalazine dose (mg/day)
Mercaptopurine dose (mg/day)
Before flare
Time of flare
After flare
660
4900
4000
75
370
9700
2000
75
640
5200
4000
75
6-TGN: 6-thioguaninenucleotides (therapeutic range 600–1200 pmol/8 × 108); 6-MMPR: 6-methylmercaptopurine-ribonucleotides (toxic
range N5700 pmol/8 × 108).
All thiopurine metabolites are measured in red blood cells.
http://dx.doi.org/10.1016/j.crohns.2014.08.003
1873-9946/© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1744
References
1. de Boer NK, Wong DR, Jharap B, de Graaf P, Hooymans PM, Mulder CJ,
et al. Dose-dependent influence of 5-aminosalicylates on thiopurine
metabolism. Am J Gastroenterol 2007;102:2747–53.
2. Jharap B, Seinen ML, de Boer NK, van Ginkel Jr, Linskens RK,
Kneppelhout JC, et al. Thiopurine therapy in inflammatory bowel
disease patients: analyses of two 8-year intercept cohorts.
Inflamm Bowel Dis 2010;16:1541–9.
3. Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret
Y, et al. Pharmacogenomics and metabolite measurement for
6-mercaptopurine therapy in inflammatory bowel disease.
Gastroenterology 2000;118:705–13.
4. Haines ML, Ajlouni Y, Irving PM, Sparrow MP, Rose R, Gearry RB,
et al. Clinical usefulness of therapeutic drug monitoring of
thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis 2011;17:1301–7.
Letter to the Editor
Greetje J. Tack⁎
Petra Waayenberg
Nanne K.H. de Boer
Department of Gastroenterology and Hepatology,
VU Medical Center, Amsterdam, The Netherlands
⁎Corresponding author at: Department of Gastroenterology and Hepatology, VU Medical Center,
PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
Tel.: +31 20 4440613; fax: +31 20 4440554.
E-mail address: [email protected].
4 August 2014