European Journal of Clinical Pharmacology

, Volume 75, Issue 12, pp 1669–1674 | Cite as

Thiopurines with low-dose allopurinol (ThiLDA)—a prospective clinical one-way crossover trial

  • S. Faraz ChavoushiEmail author
  • Bindia Jharap
  • Philip Friedrich
  • Kees Smid
  • Godefridus J. Peters
  • Mirte Malingré
Clinical Trial



Many patients with Crohn’s disease (CD) and ulcerative colitis (UC) who have a high 6-methylmercaptopurine/6-thioguanine (6-MMP/6-TGN) ratio receive allopurinol 100 mg in addition to thiopurines to optimize metabolite concentrations. However, some patients do not tolerate allopurinol at this dosage.

The aim of this study was to determine the intra-patient effect of reducing the allopurinol dosage from 100 to 50 mg, in terms of metabolite concentrations, enzyme activities, efficacy, and tolerability.


A prospective non-inferiority one-way crossover study was performed. CD and UC patients with stable disease using a thiopurine and allopurinol 100 mg were switched to 50 mg for 1 month. Primary outcomes were thiopurine metabolite concentrations. Secondary outcomes were enzyme activities of xanthine oxidase, thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyltransferase, disease activity, and tolerability.


Twenty-two patients were included. Treatment with allopurinol 50 mg compared with 100 mg resulted in a significant decrease in mean 6-TGN levels (761 to 625 pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665 pmol/8 × 108 RBC; p = 0.01). However, the mean metabolite concentrations were still therapeutic. Enzyme activities, disease activity scores, and patient experiences did not alter significantly. Generally, UC patients were more positive about their improved treatment than CD patients.


Combination therapy with 50 mg allopurinol led to a decrease of 6-TGN levels compared with 100 mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50 mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients.

Trial registration

EudraCT trial registry - number 2016-001638-84


Allopurinol Thiopurine Metabolites Tolerability Efficacy 6-TGN 6-MMP 



We thank Richard J Honeywell, Amsterdam UMC VU University Medical Center Amsterdam, Department of Medical Oncology, for his help with the enzyme assays.

Authors’ contributions

The guarantor of the article is Mr. S. Faraz Chavoushi.

Specific author contributions: Mr. Chavoushi designed the research study recruited patients, collected and analyzed the data, and wrote the paper. Mrs. Malingré contributed to the design of the study, wrote the paper, and contributed to the analysis in the laboratory. Mrs. Jharap helped recruiting patients and wrote the paper. Mr. Friederich helped recruiting patients for this research study. Mr. Peters helped writing the paper and contributed to determining enzyme activities in his laboratory together with Mr. Smid.

All authors approved the final version of the manuscript.

Compliance with ethical standards

The trial was approved by the Medical Research Ethics Committees United Netherlands (MEC-U). The trial was registered in the EudraCT trial registry (, trial number 2016-001638-84). Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Gomollon F, Dignass A, Annese V et al (2017) 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis 11:3–25CrossRefGoogle Scholar
  2. 2.
    Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, Kucharzik T, Molnár T, Raine T, Sebastian S, de Sousa HT, Dignass A, Carbonnel F, for the European Crohn’s and Colitis Organisation [ECCO] (2017) Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: Current management. J Crohns Colitis 11(7):769–784CrossRefGoogle Scholar
  3. 3.
    Jharap B, Seinen ML, de Boer NK et al (2010) Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 16:1541–1549CrossRefGoogle Scholar
  4. 4.
    Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R (1995) A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut 37:674–678CrossRefGoogle Scholar
  5. 5.
    Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK (2012) Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev:CD000478Google Scholar
  6. 6.
    Prefontaine E, Macdonald JK, Sutherland LR (2010) Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev:CD000545Google Scholar
  7. 7.
    Sparrow MP, Hande SA, Friedman S et al (2005) Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 22:441–446CrossRefGoogle Scholar
  8. 8.
    Gardiner SJ, Gearry RB, Burt MJ, Chalmers-Watson T, Chapman BA, Ross AG, Stedman CAM, Huelsen A, Barclay ML (2011) Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio. J Gastroenterol Hepatol 26:49–54CrossRefGoogle Scholar
  9. 9.
    Govani SM, Higgins PD (2010) Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD. J Crohns Colitis 4:444–449CrossRefGoogle Scholar
  10. 10.
    Dubinsky (2003) Optimizing immunomodulator therapy for inflammatory bowel disease. Curr Gastroenterol Rep 5:506–511CrossRefGoogle Scholar
  11. 11.
    Hoentjen F, Seinen ML, Hanauer SB, de Boer NKH, Rubin DT, Bouma G, Harrell LE, van Bodegraven AA (2013) Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 19:363–369CrossRefGoogle Scholar
  12. 12.
    Smith MA, Blaker P, Marinaki AM, Anderson SH, Irving PM, Sanderson JD (2012) Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis 6:905–912CrossRefGoogle Scholar
  13. 13.
    Curkovic I, Rentsch KM, Frei P, Fried M, Rogler G, Kullak-Ublick GA, Jetter A (2013) Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations. Eur J Clin Pharmacol 69:1521–1531CrossRefGoogle Scholar
  14. 14.
    Dervieux T, Meyer G, Barham R et al (2005) Liquid chromatography-tandem mass spectrometry analysis of erythrocyte thiopurine nucleotides and effect of thiopurine methyltransferase gene variants on these metabolites in patients receiving azathioprine/6-mercaptopurine therapy. Clin Chem 51:2074–2084CrossRefGoogle Scholar
  15. 15.
    Seinen ML, van Asseldonk DP, de Boer NK et al (2013) The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study. J Crohns Colitis 7:812–819CrossRefGoogle Scholar
  16. 16.
    Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB (2007) Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 5:209–214CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical PharmacyMeander Medical CenterAmersfoortThe Netherlands
  2. 2.Department of Gastroenterology and HepatologyMeander Medical CenterAmersfoortThe Netherlands
  3. 3.Department of Medical OncologyAmsterdam UMC, VU University Medical CenterAmsterdamThe Netherlands

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