Anonymous User
Login / Registration

Gastroenterologie
a hepatologie

Gastroenterology and Hepatology

Gastroent Hepatol 2021; 75(6): 508–514. doi: 10.48095/ccgh2021508.

Azathioprine in the therapy of paediatric inflammatory bowel disease – part II: pharmacodynamics, pharmacokinetics, and the possibilities of measuring its metabolites in clinical practice

Kristýna Pospíšilová1, Jiří Bronský Orcid.org  1

+ Affiliation

Summary

Background: Thiopurines (predominantly azathioprine and mercaptopurine) are widely used in paediatrics to maintain remission in the treatment of inflammatory bowel disease. After its absorption from the gastrointestinal tract, azathioprine is converted into 6 mercaptopurine in approximately 90%. Several enzymes (such as thiopurine methyltransferase, xanthine oxidase and hypoxanthine-guanine phosphoribosyl transferase) participate in its further metabolism, producing non-active methylated metabolites (6 methylmercaptopurine) and thiouric acid and active 6-thioguanine nucleotide. The concentration of these metabolites can be measured in red blood cells. Aim: To map the benefits and possibilities of thiopurine metabolites measurements in patients suffering from inflammatory bowel disease. Conclusion: The measurement of active and non-active metabolites can help evaluate the bioavailability of those drugs, identify some causes of adverse effects and reveal non-adherence.

Keywords

Crohn’s disease, merkaptopurin, pediatrie, thiopuriny, ulcerative colitis

To read this article in full, please register for free on this website.

Benefits for subscribers

Benefits for logged users

Literature

1. Schwab M, Klotz U. Pharmacokinetic considerations in the treatement of inflammatory bowel disease. Clin Pharmacokinet 2001; 40(10): 723–751. doi: 10.2165/00003088-200140100-00003.
2. Dubinsky, CM. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol 2004; 2(9): 731–743. doi: 10.1016/s1542-3565(04)00344-1.
3. Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013; 19(11): 1699–1706. doi: 10.3748/wjg.v19.i11.1699.
4. Derijks LJJ, Gilissen LPL, Engels LGJB et al. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease, implications for therapy. Ther Drug Monitor 2004; 26(3): 311–318. doi: 10.1097/00007691-200406000-00 016.
5. Cuffari C, Théoret Y, Latour S et al. 6-mercaptopurine metabolism in Crohn‘s disease: corrletion with efficacy and toxicity. Gut 1996; 39(3): 401–406. doi: 10.1136/gut.39.3.401.
6. Hindorf U, Lindqvist M, Hildebrand H et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2006; 24(2): 331–342. doi: 10.1111/j.1365-2036. 2006.02977.x.
7. Pozler O, Chládek J, Malý J et al. Steady-state of azathioprine during initiation treatement of pediatric inflammatory bowel disease. J Crohns Colitis 2010; 4(6): 623–628. doi: 10.1016/j.crohns.2010.06.005.
8. Hawwa AF, Millership JS, Colier PS et al. Development and validation of HPLC method for the rapid and simultaneous determination of 6-mercaptopurine and four of its metabolites in plasma and red blood cells. J Pharm Biomed Anal 2009; 49(2): 401–409. doi: 10.1016/j.jpba.2008.10.045.
9. Dervieux T, Blanco JG, Krynetski EY et al. Differig contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human lekemic cells. Cancer Research 2001; 61(15): 5810–5816.
10. Van Os EC, Zins BJ, Sandborn WJ et al. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration. Gut 1996; 39(1): 63–68. doi: 10.1136/gut.39.1.63.
11. Zins BJ, Sandborn WJ, McKinney JA et al. A dose-ranging study of azathioprine pharmacokinetics after single-dose administration of a delayed-release oral formulation. J Clin Pharmacol 1997; 37(1): 38–46. doi: 10.1177/0091270 09703700107.
12. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64(8): 753–767. doi: 10.1007/s00228-008-0478-6.
13. Sandborn WJ, Van Os EC, Zins BJ et al. An intravenous lading dose of azathioprine decreases the time to response in patients with Crohn‘s disease. Gastroenterology 1995; 109(6): 1808–1817. doi: 10.1016/0016-5085(95)90747-5.
14. Sandborn WJ, Tremaine WJ, Wolf DC et al. Lack of effect of intravenous administration on time to respond to AZA for steroid-treated Crohns disease. Gastroenterology 1999; 117(3): 527–535. doi: 10.1016/s0016-5085(99)70445-2.
15. Mahadevan U, Tremaine WJ, Johnson T et al. Intravenous azathioprine in severe ulcerative colitis: a pilot study. Am J Gastroenterol 2000; 95(12): 3463–3468. doi: 10.1111/ j.1572-0241.2000.03362.x.
16. Christie NT, Drake S, Meyn RE et al. 6-thioguanine-induced DNA damage as a determinant of cytotoxicity in cultured chinese hamster ovary cells. Cancer Res 1984; 44(9): 3665–3671.
17. Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatement. Biochem Pharmacol 1986; 35(20): 3533–3541. doi: 10.1016/0006-2952(86)90623-4.
18. Tiede I, Fritz G, Strand S et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003; 111(8): 1133–1145. doi: 10.1172/JCI16432.
19. Misdaq M, Ziegler S, von Ahsen N et al. Thiopurines induce oxidative stress in T-lyphocytes: a proteomic approach. Mediatros Inflamm 2015; 2015: 434825. doi: 10.1155/2015/434825.
20. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Gen 1980; 32(5): 651–662.
21. Schaeffeler E, Fisher C, Dierk B et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004; 14(7): 407–417. doi: 10.1097/01.fpc.0000114745.08559.db.
22. Breen DP, Marinaki AM, Arenas M et al. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppresive therapy following liver transplantation. Liver Transplant 2005; 11(7): 826–833. doi: 10.1002/lt.20377.
23. Yates CR, Krynetski EY, Loennechen T et al. Molecular dia­gnosis of thiopurine S-methyltransferase deficiency: gentic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126(8): 608–614. doi: 10.7326/0003-4819-126-8-199704150-00003.
24. Ding L, Zhang F, Liu H et al. Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2012; 18(1): 63–73. doi: 10.1002/ibd.21676.
25. Collie-Duguid ESR, Pritchard SC, Powrie RH et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian population. Pharmacogenetics 1999; 9(1): 37–42. doi: 10.1097/00008571-199902000-00006.
26. Jun JB, Cho DY, Kang C et al. Thiopurine S-methyltransferase polymorphisms and the relatioship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Experiment Rheum 2005; 23(6): 873–876.
27. Ruemmelle FM, Veres G, Kolho KL et al. Consensus guidelines of ECCO/ESPHGAN on the medical management of pediatric Crohn‘s dis­ease. J Crohns Colitis 2014; 8(10): 1179–1207. doi: 10.1016/j.crohns.2014.04.005.
28. Lennard L, Lilleyman JS, Van Loon J et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990; 336(8709): 225–229. doi: 10.1016/0140-6736(90)91745-v.
29. Poon SS, Asher R, Jackson R et al. Body mass index and smoking affect thioguanine nucleotide levels in inflammatory bowel disease. J Crohns Colitis 2015; 9(8): 640–646. doi: 10.1093/ecco-jcc/jjv084.
30. McLeod HL, Krynetski EY, Wilimas JA et al. Higher activity of polymorphis thiopurine S-methyltransferase in erytrocytes from neonates compared to adults. Pharmacogenetics 1995; 5(5): 281–286. doi: 10.1097/000 08571-199510000-00003.
31. Serpe L, Calvo PL, Muntoni E et al. Thiopurine S-methyltransferase pharmacogenetics i a large-scale healthy Italian-Caucasian population: differences in enzyme activity. Pharmacogenomics 2009; 10(11): 1753–1765. doi: 10.2217/pgs.09.103.
32. Stocco G, Martelossi S, Arrigo S et al. Multicentric case-control study on azathioprine dose and pharmacokinetics in early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis 2017; 23(4): 628–634. doi: 10.1097/MIB.00000 00000001051.
33. Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechansim for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995; 39(4): 456–459. doi: 10.1111/j.1365-2125.1995.tb04478.x.
34. Lowry PW, Szumlanski CL, Weinshilboum RM et al. Balsalazide and azathioprine or 5-mercaptopurine: evidence for potentially serious drug interaction. Gastroenterology 1999; 116(6): 1505–1506. doi: 10.1016/s0016-5085(99)70524-x.
35. Lewis LD, Benin A, Szumlanski CL et al. Olsalazine and 6-mercaptopurine-related bone marrow suppression: a psosible drug-drug interaction. Clin Pharmacol Ther 1997; 62(4): 464–475. doi: 10.1016/S0009-9236(97)90125-9.
36. Dewit O, Vanheuverzvyn R, Desager JP et al. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn‘s disease. Aliment Pharmacol Ther 2002; 16(1): 79–85. doi: 10.1046/j.1365-2036.2002.01156.x.
37. Lysaa RA, Giverhaug T, Wold HL et al. Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol 1996; 49 (5): 393–396. doi: 10.1007/s002280050038.
38. Xin HW, Fisher C, Schwab M et al. Thiopurine S-methyltransferase as a target for drug interactions. Eur J Clin Pharmacol 2005; 61(5–6): 395–398. doi: 10.1007/s00228-005-0950-5.
39. Ansari A, Hassan C, Duley J et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(10): 1743–1750. doi: 10.1046/j.1365-2036.2002.01353.x.
40. Cuffari C, Dassopoulos T, Turnbough L et al. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2004; 2(5): 410–417. doi: 10.1016/s1542-35 65(04)00127-2.
41. Dubinsky MC, Yang H, Hassard PV et al. 6-MP metabolite profiles provide a bio­chemical explanantion for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002; 122(4): 904–915. doi: 10.1053/gast.2002.32420.
42. Yan L, Zhang S, Eiff B et al. Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clin Pharmacol Ther 2000; 68(2): 210–219. doi: 10.1067/mcp.2000.108674.
43. Munnig-Schmidt E, Zhang M, Mulder CJ et al. Late-onset rise of 6-MMP metabolites in IBD patients on azathioprine or mercaptopurine. Inflamm Bowel Dis 2018; 24(4): 892–896. doi: 10.1093/ibd/izx081.
44. Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008; 14(12): 1678–1682. doi: 10.1002/ibd.20522.
45. Duley JA, Chocair PR, Florin THJ. Observations on the use of allopurinol in combination with aazthioprine or mercaptopurine. Aliment Pharmacol Ther 2005; 22(11–12): 1161–1162. doi: 10.1111/j.1365-2036.2005.02703.x.
46. Blaker PA, Arenas-Hernandez M, Smith MA et al. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol 2013; 86(4): 539–547. doi: 10.1016/j.bcp.2013.06.002.
47. Marinaki AM, Ansari A, Duley JA et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14(3): 181–187. doi: 10.1097/00008571-200403000-00006.
48. Maeda T, Sumi S, Ueta A et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population. Mol Genet Metab 2005; 85(4): 271–279. doi: 10.1016/j.ymgme.2005.03.011.
49. Gearry RB, Roberts RL, Barclay ML et al. Lack of association between the ITP 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 2004; 14(11): 779–781. doi: 10.1097/00008571-200411000-00010.
50. Dervieux T, Boulieu R. Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC. Clin Chem 1998; 44(3): 551–555.
51. de Nikoló A, Agnesod D, Simiele M et al. UPLC-MS/MS method for quantification of the aazthioprine metabolites 6-mercaptoguanosine and 6-methylmercaptopurine riboside in peripheral blood mononuclear cells. J Pharm Biomed Anal 2014; 98: 271–278. doi: 10.1016/j.jpba.2014.05.040.
52. Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48(5): 642–646. doi: 10.1136/gut.48.5.642.
53. Osterman MT, Kundu R, Lichtenstein GR et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006; 130(4): 1047–1053. doi: 10.1053/j.gastro.2006.01.046.
54. Moreau AC, Paul S, Del Tedesco E et al. Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory bowel disease: a meta-analysis. Inflamm Bowel Dis 2014; 20(3): 464–471. doi: 10.1097/01.MIB.0000439068.71126.00.
55. Gupta P, Gokhale R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Garoenterol Nutr 2001; 33(4): 450–454. doi: 10.1097/00005176-200110000-00006.
56. Nguyen T-V-A, Vu DH, Nguyen T-M-H et al. Exploring association of 6-thioguanine nucleotide levels and other predictive factors with theraputic response to azathioprine in pediatric patients with IBD using multilevel analysis. Inflamm Bowel Dis 2013; 19(11): 2404–2410. doi: 10.1097/MIB.0b013e3182a508c6.
57. Fanbing Z, Xiang G, Liang D et al. Prospective evaluation of pharmacogenomics and metabolite measurements upon azathioprine therapy in inflammatory bowel disease. Medicine 2016; 95(15): e3326. doi: 10.1097/MD.0000 000000003326.
58. Turner D, Ruemmele FM, Orlanski-Meyer E et al. Management of paediatric ulcerative colitis, part 1: ambulatory care- an evidence-based guideline from ECCO and ESPGHAN. J Pediatr Garoenterol Nutr 2018; 67(2): 257–291. doi: 10.1097/MPG.0000000000002035.
59. Dubinsky MC, Lamothe S, Ying Yang G et al. Pharmacogenomics and metabolite mea­­- surement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118(4): 705–713. doi: 10.1016/s0016-5085(00)70140-5.
60. Mardini HE, Arnold GL. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical practice setting. J Clin Gastroenterol 2003; 36(5): 390–395. doi: 10.1097/00004836-200305000-00005.
61. Dassopoulos T, Dubinsky MC, Bentsen JL et al. Randomised clinical trial: individualized versus weight-based dosing of azathioprine in Crohn’s disease. Aliment Pharmacol Ther 2014; 39(2): 163–175. doi: 10.1111/apt.12555.
62. Reinshagen M, Schütz E, Armstrong VW et al. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from randomized, controlled, open trial. Clin Chem 2007; 53(7): 1306–1314. doi: 10.1373/clinchem.2007.086215.
63. Smith MA, Blaker P, Marinaki AM et al. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis 2012; 6(9): 905–912. doi: 10.1016/j.crohns.2012.02.007.
64. Sparrow MP, Hande SA, Friedman S et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007; 5(2): 209–214. doi: 10.1016/j.cgh.2006.11.020.
65. Gerich ME, Quiros JA, Marcin JP et al. A prospective evaluation of the impact of allopurinol in pediatric and adult IBD patients with preferentioal metabolism of 6-mercaptopurine to 6-methylmercaptopurine. J Crohns Colitis 2010; 4(5): 546–552. doi: 10.1016/j.crohns.2010.03.004.
66. Friedman AB, Brown SJ, Bampton P et al. Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA study). Aliment Pharmacol Ther 2018; 47(8): 1092–1102. doi: 10.1111/apt.14571.
67. Shih DQ, Nguyen M, Zheng L et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther 2012; 36(5): 449–458. doi: 10.1111/j.1365-2036.2012.05206.x.
68. Roblin X, Williet N, Peyrin-Biroulet L. Thiopurine metabolism in the era of combotherapy. Inflamm Bowel Dis 2015; 21(4): 951–961. doi: 10.1097/MIB.0000000000000737.
69. Yarur AJ, Kubiliun MJ, Czul F et al. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin Gastroenterol Hepatol 2015; 13(6): 1118–1124. doi: 10.1016/j.cgh.2014.12.026.
70. Pospisilova K, Siroka J, Karaskova E et al. Is it useful to monitor thiopurine metabolites in paediatric Crohn’s disease patients on combination therapy? A multicenter prospective observational study. Pediatr Drugs 2021; 23(2): 183–194. doi: 10.1007/s40272-021-00439-1.

Credited self-teaching test