Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment

Journal of Crohn's and Colitis

Volumn 6, Issue 1, 2012, Pages 95-101

  Van Asseldonk, Dirk P ^a   Seinen, Margien L ^a   De Boer, Nanne K H ^a   Van Bodegraven, Ad A ^a   Mulder, Chris J ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

6 Mercaptopurine; 6 Methyl mercaptopurine; 6 Thioguanine; Azathioprine; Hepatotoxicity; Inflammatory bowel disease

Indexed keywords

6 MERCAPTOPURINE DERIVATIVE; 6 METHYLTHIOINOSINE; ADALIMUMAB; ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE; AZATHIOPRINE; BILIRUBIN; BUDESONIDE; GAMMA GLUTAMYLTRANSFERASE; MESALAZINE; PREDNISOLONE; TIOGUANINE;

ADULT; ARTHRALGIA; ARTICLE; BONE MARROW TOXICITY; CLINICAL ARTICLE; CLOSTRIDIUM DIFFICILE ENTEROCOLITIS; COLITIS; CONCENTRATION (PARAMETERS); CROHN DISEASE; DISEASE COURSE; DISEASE DURATION; DRUG METABOLISM; ENTEROCOLITIS; ERYTHROCYTE; FEMALE; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LABORATORY TEST; LIVER TOXICITY; MALE; MYALGIA; NAUSEA; OUTCOME ASSESSMENT; PANCOLITIS; PRIORITY JOURNAL; PROCTITIS; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; SHORT COURSE THERAPY; TREATMENT CONTRAINDICATION; TREATMENT DURATION; TREATMENT FAILURE; TREATMENT WITHDRAWAL; ULCERATIVE COLITIS;

6-MERCAPTOPURINE; ANTIMETABOLITES, ANTINEOPLASTIC; AZATHIOPRINE; DRUG-INDUCED LIVER INJURY; FEMALE; HUMANS; INFLAMMATORY BOWEL DISEASES; MALE; RETROSPECTIVE STUDIES; THIOGUANINE; TREATMENT OUTCOME;

EID: 84855950727     PISSN: 18739946     EISSN: 18764479     Source Type: Journal    
DOI: 10.1016/j.crohns.2011.07.009     Document Type: Article

References (28)

1. Jharap B., Seinen M.L., de Boer N.K.H., van Ginkel J.R., Linskens R.K., Kneppelhout J.C., Mulder C.J., Van Bodegraven A.A. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010, 16:1541-1549.
2. Schaeffeler E., Fischer C., Brockmeier D., Wernet D., Moerike K., Eichelbaum M., Zanger U.M., Schwab M. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004, 14:407-417.
3. Dubinsky M.C., Lamothe S., Yang H.Y., Targan S.R., Sinnett D., Theoret Y., Seidman E.G. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000, 118:705-713.
4. Dubinsky M.C., Yang H., Hassard P.V., Seidman E.G., Kam L.Y., Abreu M.T., Targan S.R., Vasiliauskas E.A. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002, 122:904-915.
5. Gardiner S.J., Gearry R.B., Burt M.J., Ding S.L., Barclay M.L. Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides. Eur J Gastroenterol Hepatol 2008, 20:1238-1242.
6. Dignass A., Van Assche G., Lindsay J.O., Lemann M., Soderholm J., Colombel J.F., Danese S., D'Hoore A., Gassull M., Gomollon F., Hommes D.W., Michetti P., O'Morain C., Oresland T., Windsor A., Stange E.F., Travis S.P. The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management. J Crohns Colitis 2010, 4:28-62.
7. Sparrow M.P., Hande S.A., Friedman S., Cao D., Hanauer S.B. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007, 5:209-214.
8. Herrlinger K.R., Deibert P., Schwab M., Kreisel W., Fischer C., Fellermann K., Stange E.F. Remission maintenance by tioguanine in chronic active Crohn's disease. Aliment Pharmacol Ther 2003, 17:1459-1464.
9. Van Asseldonk D.P., Jharap B., Kuik D.J., De Boer N.K., Westerveld B.D., Russel M.G., Kubben F.J., Van Bodegraven A.A., Mulder C.J. Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis. Dig Liver Dis 2011, 43:110-115.
10. Lennard-Jones J.E. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl 1989, 170:2-6.
11. De Boer N.K., Reinisch W., Teml A., Van Bodegraven A.A., Schwab M., Lukas M., Ochsenkuhn T., Petritsch W., Knoflach P., Almer S., Van der Merwe S.W., Herrlinger K.R., Seiderer J., Vogelsang H., Mulder C.J. 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party. Digestion 2006, 73:25-31.
12. US Department of Health and Human Services, National Institute of Health, National Cancer institute Common terminology criteria for adverse events v4.03 Accessed March 2011 at. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
13. 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, 44:551-555.
14. De Graaf P., Vos R.M., De Boer N.H., Sinjewel A., Jharap B., Mulder C.J., Van Bodegraven A.A., Veldkamp A.I. Limited stability of thiopurine metabolites in blood samples: relevant in research and clinical practise. J Chromatogr B Analyt Technol Biomed Life Sci 2010, 878:1437-1442.
15. Lennard L., Singleton H.J. High-performance liquid chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine: quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmercaptopurine metabolites in a single sample. J Chromatogr 1992, 583:83-90.
16. Shipkova M., Armstrong V.W., Wieland E., Oellerich M. Differences in nucleotide hydrolysis contribute to the differences between erythrocyte 6-thioguanine nucleotide concentrations determined by two widely used methods. Clin Chem 2003, 49:260-268.
17. Harvey R.F., Bradshaw M.J. Measuring Crohn's disease activity. Lancet 1980, 1:1134-1135.
18. Lichtiger S., Present D.H. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990, 336:16-19.
19. Bonaz B., Boitard J., Marteau P., Lemann M., Coffin B., Flourie B., Belaiche J., Cadiot G., Metman E.H., Cortot A., Colombel J.F. Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine. Aliment Pharmacol Ther 2003, 18:401-408.
20. Bastida G., Nos P., Aguas M., Beltran B., Rubin A., Dasi F., Ponce J. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005, 22:775-782.
21. Menor C., Fernandez-Moreno M.D., Fueyo J.A., Escribano O., Olleros T., Arriaza E., Cara C., Lorusso M., Di paola M., Roman I.D., Guijarro L.G. Azathioprine acts upon rat hepatocyte mitochondria and stress-activated protein kinases leading to necrosis: protective role of N-acetyl-l-cysteine. J Pharmacol Exp Ther 2004, 311:668-676.
22. De Boer N.K., Jharap B., Mulder C., Van Bodegraven A.A. Low and adequately dosed 6-thioguanine: not so bad after all. Inflamm Bowel Dis 2008, 14:1166-1167.
23. Geller S.A., Dubinsky M.C., Poordad F.F., Vasiliauskas E.A., Cohen A.H., Abreu M.T., Tran T., Martin P., Vierling J.M., Targan S.R. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 2004, 28:1204-1211.
24. Gilissen L.P., Derijks L.J., Driessen A., Bos L.P., Hooymans P.M., Stockbrugger R.W., Engels L.G. Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?. Dig Liver Dis 2007, 39:156-159.
25. Van Asseldonk D.P., Jharap B., De Boer N.H., Zondervan P.E., Bloemena E., Den Hartog G., Westerveld B.D., kolkman J.J., Engels L.G., Van Bodegraven A.A., Mulder C. Liver histology of IBD patients who are treated with 6-thioguanine due to failure of conventional thiopurines reveals very few cases of nodular regenerative hyperplasia. Gastroenterology 2010, 138:S-62.
26. Hindorf U., Lindqvist M., Hildebrand H., Fagerberg U., Almer S. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2006, 24:331-342.
27. Sparrow M.P. Use of allopurinol to optimize thiopurine immunomodulator efficacy in inflammatory bowel disease. Gastroenterol Hepatol 2008, 4:505-511.
28. Ansari A., Patel N., Sanderson J., O'Donohue J., Duley J.A., Florin T.H. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010, 31:640-647.