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Therapeutic Agents and Patient Characteristics Affecting Metabolism of Thiopurines in Patients with Inflammatory Bowel Disease

Masato Aizawa, Kohei Suzuki, Yuki Nakajima, Kenichi Utano, Kana Tamazawa, Kenta Ueda, Jun Wada, Kentaro Sato, Goro Shibukawa, Noriko Tanaka, Kazutomo Togashi

Author information

  • Masato Aizawa

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Kohei Suzuki

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Yuki Nakajima

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Kenichi Utano

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Kana Tamazawa

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Kenta Ueda

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Jun Wada

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Kentaro Sato

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Goro Shibukawa

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

  • Noriko Tanaka

    Health Data Science Research Section, Tokyo Metropolitan Institute of Gerontology
    Clinical Research Center, Fukushima Medical University Hospital, Fukushima Medical University

  • Kazutomo Togashi

    Department of Coloproctology and Gastroenterology, Aizu Medical Center Fukushima Medical University

Abstract

Objectives:In inflammatory bowel disease therapy, thiopurines have been essential.　However, several reports have investigated factors affecting thiopurine metabolism to date.　This study investigated factors affecting intracellular concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) in a real-world setting.


Methods:Between May 2013 and October 2021 in one institution, 44 patients (median age 44 years;male 35, female 9;ulcerative colitis 32, Crohn’s disease 12) receiving thiopurines were reviewed.　Intracellular 6-TGN/6-MMP concentrations were measured by high-performance liquid chromatography, and the initial measurement in each patient was used for the study.


Results:The 6-TGN level was significantly higher in females, with mild disease activity, absence of NUDT15 polymorphism, and allopurinol administration.　A higher trend was observed with high thiopurine dosage (>50 mg).　6-MMP levels were significantly lower with concomitant use of time-dependent 5-aminosalicylic acid (5-ASA) and allopurinol, and higher with high thiopurine dosage.　On multivariate analysis of variance, logarithmically transformed 6-TGN levels were significantly higher in females, with high thiopurine dosage, and allopurinol administration.　Similarly, logarithmically transformed 6-MMP levels were significantly higher with time-dependent 5-ASA administration and high thiopurine dosage.


Conclusions:Patients who received allopurinol, a high dose of thiopurine, or were female showed higher 6-TGN levels.

The cintent of reseach paper

References

1. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A.　Epidemiology and Natural History of Inflammatory Bowel Diseases.　Gastroenterology, 140:1785-1794, 2011.


2. D Laharie, J Filippi, X Roblin, et al.　Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab:a multicenter experience.　Aliment Pharmacol Ther, 37:998-1004, 2013.


3. Colombel JF, Rutgeerts P, Reinisch W, et al.　Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.　Gastroenterology, 141:1194-1201, 2011.


4. Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P.　Efficacy of immunosuppressive therapy for inflammatory bowel disease:a systematic review and meta-analysis.　Am J Gastroenterol, 106:630-642, 2011.


5. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK.　Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.　Cochrane Database Syst Rev, 12;(9):CD000478, 2012.


6. Burchenal JH, Murphy ML, Ellison RR, et al.　Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases.　Blood, 8:965-999, 1953.


7. Bowen GE, Irons GV Jr, Rhodes JB, Kirsner JB.　Early experiences with azathioprine in ulcerative colitis;a note of caution.　JAMA, 195:460-464, 1966.


8. Khan KJ, Dubinsky MC, Ford AC, et al.　Efficacy of immunosuppressive therapy for inflammatory bowel disease:a systematic review and meta-analysis.　Am J Gastroenterol, 106(4):630-642, 2011.


9. Chande N, Tsoulis DJ, MacDonald JK.　Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease.　Cochrane Database Syst Rev, 30;(4):CD000545, 2013.


10. Sparrow MP, Hande SA, Friedman S, et al.　Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine.　Aliment Pharmacol Ther, 22:441-416, 2005.


11. Gao X, Zhang FB, Ding L, Liu H, et al.　The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.　Eur J Gastroenterol Hepatol, 24:958-964, 2012.


12. Blaker PA, Arenas-Hernandez M, Smith MA, Shobowale-Bakre EA, Fairbanks L, Irving PM.　Mechanism of allopurinol induced TPMT inhibition.　Biochem Pharm, 86:539-547, 2013.


13. Kopylov U, Battat R, Benmassaoud A, Paradis-Surprenant L, Seidman EG.　Hematologic indices as surrogate markers for monitoring thiopurine therapy in IBD.　Dig Dis Sci, 60:478-484, 2015.


14. Lowry PW, Franklin CL, Weaver AL, et al.　Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.　Gut, 49:656-664, 2001.


15. Morikubo H, Kobayashi T, Ozaki R, et al.　Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.　J Gastroenterol Hepatol, 36:2116-2124, 2021.


16. C Cuffari, S Hunt, T Bayless.　Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease.　Gut, 48:642-646, 2001.


17. Chevaux JB, Biroulet LP, and Sparrow MP.　Optimizing Thiopurine Therapy in Inflammatory Bowel Disease.　Inflamm Bowel Dis, 17:1428-1435, 2011.


18. Sandborn WJ.　Rational dosing of azathioprine and 6-mercaptopurine.　Gut, 48:591-592, 2001.


19. Turbayne AK, Sparrow MP.　Low-Dose Azathioprine in Combination with Allopurinol:The Past, Present and Future of This Useful Duo.　Dig Dis Sci, 67:5382-5391, 2022.


20. Hanai H, Iida T, Takeuchi K, et al.　Thiopurine maintenance therapy for ulcerative colitis:the clinical significance of monitoring 6-thioguanine nucleotide.　Inflamm Bowel Dis, 16:1376-1381, 2010.


21. Kakuta Y, Kawai Y, Okamoto D, et al.　NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease:a multicenter study.　J Gastroenterol, 53:1065-1078, 2018.


22. Asada A, Nishida A, Shioya M, et al.　NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease.　J Gastroenterol, 51:22-29, 2016.

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