Background/Aims: Thiopurines are key drugs in maintenance therapy for treating inflammatory bowel disease (IBD). Time-dependent 5-aminosalicylates (5-ASA) releasing preparations (time-dependent 5-ASA) increase 6-thioguanine nucleotide (6-TGN), an active metabolite of thiopurines. However, the effects of pH-dependent 5-ASA releasing preparations (pH-dependent 5-ASA) on thiopurine metabolism were not reported. Methods: We conducted a retrospective study of 134 IBD patients who received thiopurine treatment. The 6-methylmercaptopurine (6-MMP)/6-TGN values after taking the same dose of thiopurine preparations for at least 28 days were included. Results: There was a significant decrease in the 6-MMP/6-TGN ratio in time-dependent 5-ASA compared with group without 5-ASA preparations and the pH-dependent 5-ASA group (p = 0.008 and < 0.001 respectively). Spearman’s rank correlation coefficient indicated a negative relationship between the daily oral dose of time-dependent 5-ASA and the 6-MMP/6-TGN ratio (r = –0.362, p = 0.003). Multivariate logistic regression analysis was performed in the groups with 6-MMP/6-TGN ratios of 1 or more and less than 1. The use of time-dependent 5-ASA and concomitant allopurinol negatively affected the independent 6-MMP/6-TGN ratio (p = 0.006 and 0.007 respectively). Conclusion: Our study revealed that time-dependent but not pH-dependent 5-ASA decreases the 6-MMP/6-TGN ratio. We also confirmed that concomitant allopurinol results in a low 6-MMP/6TGN ratio.

Journal Section:
Original Paper
Keywords:
Mesalazine, Crohn’s disease, Ulcerative colitis
1.
Hibi T, Ogata H: Novel pathophysiological concepts of inflammatory bowel disease. J Gastroenterol 2006; 41: 10–16.
2.
Mosli MH, Sandborn WJ, Kim RB, Khanna R, Al-Judaibi B, Feagan BG: Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol 2014; 109: 994–1004.
3.
Andoh A, Tsujikawa T, Ban H, Hashimoto T, Bamba S, Ogawa A, Sasaki M, Saito Y, Fujiyama Y: Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2008; 23: 1373–1377.
4.
Hanai H, Iida T, Takeuchi K, Arai O, Watanabe F, Abe J, Maruyama Y, Oohata A, Ikeya K, Kageoka M, Miwa I, Yoshirou S, Hosoda Y, Kubota T: Thiopurine maintenance therapy for ulcerative colitis: The clinical significance of monitoring 6-thioguanine nucleotide. Inflamm Bowel Dis 2010; 16: 1376–1381.
5.
Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA: 6-mp metabolite profiles provide a biochemical explanation for 6-mp resistance in patients with inflammatory bowel disease. Gastroenterol 2002; 122: 904–915.
6.
Hindorf U, Lindqvist M, Peterson C, Soderkvist P, Strom M, Hjortswang H, Pousette A, Almer S: Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 2006; 55: 1423–1431.
7.
Jharap B, Seinen ML, de Boer NK, van Ginkel JR, Linskens RK, Kneppelhout JC, Mulder CJ, van Bodegraven AA: Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010; 16: 1541–1549.
8.
Appell ML, Wagner A, Hindorf U: A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol. J Crohns Colitis 2013; 7: 510–513.
9.
Amin J, Huang B, Yoon J, Shih DQ: Update 2014: Advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis 2015; 21: 445–452.
10.
Gao X, Zhang FB, Ding L, Liu H, Wang XD, Chen BL, Bi HC, Xiao YL, Zhao LZ, Chen MH, Huang M, Hu PJ: The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 2012; 24: 958–964.
11.
de Boer NK, Wong DR, Jharap B, de Graaf P, Hooymans PM, Mulder CJ, Rijmen F, Engels LG, van Bodegraven AA: Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism. Am J Gastroenterol 2007; 102: 2747–2753.
12.
de Graaf P, de Boer NK, Wong DR, Karner S, Jharap B, Hooymans PM, Veldkamp AI, Mulder CJ, van Bodegraven AA, Schwab M: Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy. Br J Pharmacol 2010; 160: 1083–1091.
13.
Szumlanski CL, Weinshilboum RM: Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995; 39: 456–459.
14.
Xin H, Fischer C, Schwab M, Klotz U: Effects of aminosalicylates on thiopurine s-methyltransferase activity: an ex vivo study in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005; 21: 1105–1109.
15.
Dilger K, Schaeffeler E, Lukas M, Strauch U, Herfarth H, Muller R, Schwab M: Monitoring of thiopurine methyltransferase activity in postsurgical patients with crohn’s disease during 1 year of treatment with azathioprine or mesalazine. Ther Drug Monit 2007; 29: 1–5.
16.
Coskun M, Steenholdt C, de Boer NK, Nielsen OH: Pharmacology and optimization of thiopurines and methotrexate in inflammatory bowel disease. Clin Pharmacokinet 2016; 55: 257–274.
17.
Gardiner SJ, Gearry RB, Burt MJ, Chalmers-Watson T, Chapman BA, Ross AG, Stedman CA, Huelsen A, Barclay ML: Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio. J Gastroenterol Hepatol 2011; 26: 49–54.
18.
Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB: Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005; 22: 441–446.
19.
Seinen ML, de Boer NK, Smid K, van Asseldonk DP, Bouma G, van Bodegraven AA, Peters GJ: Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series. Nucleosides Nucleotides Nucleic Acids 2011; 30: 1085–1090.
20.
Seinen ML, van Asseldonk DP, de Boer NK, Losekoot N, Smid K, Mulder CJ, Bouma G, Peters GJ, van Bodegraven AA: 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 2013; 7: 812–819.
21.
Goldberg R, Irving PM: Toxicity and response to thiopurines in patients with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9: 891–900.
22.
Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DP, Liu J, Song K: A common missense variant in nudt15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014; 46: 1017–1020.
23.
Asada A, Nishida A, Shioya M, Imaeda H, Inatomi O, Bamba S, Kito K, Sugimoto M, Andoh A: Nudt15 r139c-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol 2016; 51: 22–29.
24.
Derijks LJ, Gilissen LP, Engels LG, Bos LP, Bus PJ, Lohman JJ, van Deventer SJ, Hommes DW, Hooymans PM: Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit 2006; 28: 45–50.
25.
Haglund S, Taipalensuu J, Peterson C, Almer S: Impdh activity in thiopurine-treated patients with inflammatory bowel disease - relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol 2008; 65: 69–77.
26.
Van Dieren JM, Hansen BE, Kuipers EJ, Nieuwenhuis EE, Van der Woude CJ: Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26: 643–652.
27.
Uchiyama K, Nakamura M, Kubota T, Yamane T, Fujise K, Tajiri H: Thiopurine ­s-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment. J Gastroenterol 2009; 44: 197–203.
28.
Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, van Kampen AH, Curvers WL, Cohn D, van Deventer SJ, Hommes DW: Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 2006; 4: 44–49.
29.
Kurzawski M, Dziewanowski K, Lener A, Drozdzik M: TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol 2009; 65: 533–540.
30.
Allorge D, Hamdan R, Broly F, Libersa C, Colombel JF: ITPA genotyping test does not improve detection of crohn&apos;s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut 2005; 54: 565.
31.
Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C: Azathioprine or 6-mercaptopurine for inducing remission of crohn’s disease. Cochrane Database Syst Rev 2000;CD000545.
32.
Pike MG, Franklin CL, Mays DC, Lipsky JJ, Lowry PW, Sandborn WJ: Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood. J Chromatogr B Biomed Sci Appl 2001; 757: 1–9.
33.
Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y, Hirai F, Yao K: Adverse reactions to azathioprine cannot be predicted by thiopurine s-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009; 24: 1258–1264.
34.
Ban H, Andoh A, Imaeda H, Kobori A, Bamba S, Tsujikawa T, Sasaki M, Saito Y, Fujiyama Y: The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease. J Gastroenterol 2010; 45: 1014–1021.
35.
Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM, Shobowale-Bakre el-M, Escuredo E, Fairbanks LD, Sanderson JD: Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14: 181–187.
36.
Higaki Y, Nakayama S, Tanaka Y: Phase i clinical trial of oral modified releasing mesalazine (n-5asa), single dose study. Yakuri To Chiryo 1994; 22: 2467.
37.
Ito H, Furuta S, Sasaki H, Yoshida T, Takano Y, Hibi T: Pharmacokinetics and safety of single and multiple doses of asacol tablets in Japanese healthy volunteers. Adv Ther 2009; 26: 749–761.
38.
Shih DQ, Nguyen M, Zheng L, Ibanez P, Mei L, Kwan LY, Bradford K, Ting C, Targan SR, Vasiliauskas EA: Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-mmp metabolism. Aliment Pharmacol Ther 2012; 36: 449–458.
© 2019 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2019
You do not currently have access to this content.