Influences of Thiopurine Methyltransferase Genotype and Activity on Thiopurine-induced Leukopenia in Korean Patients With Inflammatory Bowel Disease:A Retrospective Cohort Study

Journal of Clinical Gastroenterology

Volumn 44, Issue 10, 2010, Pages e242-e248

  Kim, Jae Hak ^a   Cheon, Jae Hee ^a   Hong, Seong Soo ^b   Eun, Chang Soo ^b   Byeon, Jeong Sik ^b   Hong, Sung Yi ^c   Kim, Bo Young ^c   Kwon, Soon ho ^c   Kim, Seung Won ^c   Han, Dong Soo ^c   Yang, Suk Kyun ^c   Kim, Won Ho ^c  

^a Dongguk University College of Medicine   (South Korea)

^b Seoul Medical Science Institute   (South Korea)

^c Hanyang University Guri Hospital   (South Korea)

Author keywords

6 mercaptopurine; Azathioprine; Inflammatory bowel disease; Leukopenia; Thiopurine methyltransferase

Indexed keywords

AZATHIOPRINE; MERCAPTOPURINE; MESALAZINE; THIOPURINE METHYLTRANSFERASE;

ADULT; APPETITE; ARTICLE; COHORT ANALYSIS; CONTROLLED STUDY; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SUBSTITUTION; DRUG TOLERABILITY; DRUG WITHDRAWAL; ENTERITIS; ENZYME ACTIVITY; FEMALE; GENOTYPE; HETEROZYGOSITY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HOMOZYGOSITY; HUMAN; KOREA; LEUKOPENIA; LIQUID CHROMATOGRAPHY; MAJOR CLINICAL STUDY; MALE; MASS SPECTROMETRY; NAUSEA; PRIORITY JOURNAL; RISK FACTOR; SIDE EFFECT; VOMITING;

6-MERCAPTOPURINE; ACADEMIC MEDICAL CENTERS; ADOLESCENT; ADULT; ANTI-INFLAMMATORY AGENTS; ASIAN CONTINENTAL ANCESTRY GROUP; CHI-SQUARE DISTRIBUTION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; FEMALE; GASTROINTESTINAL AGENTS; GENETIC PREDISPOSITION TO DISEASE; HETEROZYGOTE; HOMOZYGOTE; HUMANS; INFLAMMATORY BOWEL DISEASES; KAPLAN-MEIER ESTIMATE; LEUKOPENIA; MALE; METHYLTRANSFERASES; PHENOTYPE; PROPORTIONAL HAZARDS MODELS; PYROPHOSPHATASES; REPUBLIC OF KOREA; RETROSPECTIVE STUDIES; RISK ASSESSMENT; RISK FACTORS; TANDEM MASS SPECTROMETRY; TREATMENT OUTCOME; YOUNG ADULT;

EID: 77958489771     PISSN: 01920790     EISSN: 15392031     Source Type: Journal    
DOI: 10.1097/MCG.0b013e3181d6baf5     Document Type: Article

References (42)

1. Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut. 1995;37:674-678.
2. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev. 2000;2:CD000067.
3. Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Syst Rev. 2000;2:CD000545.
4. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485-489.
5. Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;1:CD000478.
6. Prefontaine E, Sutherland LR, Macdonald JK, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2009;1:CD000067.
7. Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783-1800.
8. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther. 1989;46:149-154.
9. Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705-713.
10. Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16:1743-1750.
11. Ishioka S, Hiyama K, Sato H, et al. Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. Intern Med. 1999;38:944-947.
12. Hibi T, Naganuma M, Kitahora T, et al. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol. 2003;38:740-746.
13. Hindorf U, Lindqvist M, Peterson C, et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut. 2006;55:1423-1431.
14. Gisbert JP, Nino P, Rodrigo L, et al. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol. 2006;101:2769-2776.
15. Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4:44-49.
16. Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118:1025-1030.
17. Schwab M, Schaffeler E, Marx C, et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics. 2002;12:429-436.
18. Palmieri O, Latiano A, Bossa F, et al. Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines' toxicity and efficacy. Aliment Pharmacol Ther. 2007;26:737-745.
19. Winter JW, Gaffney D, Shapiro D, et al. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2007;25:1069-1077.
20. Marinaki AM, Duley JA, Arenas M, et al. Mutation in the ITPA gene predicts intolerance to azathioprine. Nucleosides Nucleotides Nucleic Acids. 2004;23:1393-1397.
21. Tai HL, Krynetski EY, Yates CR, et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet. 1996;58:694-702.
22. Kim JH, Cheon JH, Kim WH. The frequency and the course of the adverse effects of azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel disease. Korean J Gastroenterol. 2008;51:291-297.
23. Lee HJ, Yang S-K, Kim k-J, et al. The Safety and Efficacy of Azathioprine and 6-Mercaptopurine in the Treatment of Korean Patients with Crohn's Disease. Intest Res. 2009;7:22-31.
24. Cheon JH, Kim JH, Kim BY, et al. Allele frequency of thiopurine methyltransferase and inosine triphosphate pyrophosphatase gene polymorphisms in Korean patients with inflammatory bowel diseases. Hepatogastroenterology. 2009;56:421-423.
25. Schaeffeler E, Lang T, Zanger UM, et al. High-throughput genotyping of thiopurine S-methyltransferase by denaturing HPLC. Clin Chem. 2001;47:548-555.
26. Sasaki T, Goto E, Konno Y, et al. Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals. Drug Metab Pharmacokinet. 2006;21:332-336.
27. Khalil MN, Erb N, Khalil PN, et al. Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;821:105-111.
28. Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999;9:37-42.
29. Kumagai K, Hiyama K, Ishioka S, et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics. 2001;11:275-278.
30. Jun JB, Cho DY, Kang C, et al. Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Exp Rheumatol. 2005;23:873-876.
31. Otterness D, Szumlanski C, Lennard L, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997;62:60-73.
32. Kader HA, Wenner WJ Jr, Telega GW, et al. Normal thiopurine methyltransferase levels do not eliminate 6-mercaptopurine or azathioprine toxicity in children with inflammatory bowel disease. J Clin Gastroenterol. 2000;30:409-413.
33. Cao H, Hegele RA. DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J Hum Genet. 2002;47:620-622.
34. Van Dieren JM, Hansen BE, Kuipers EJ, et al. Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2007;26:643-652.
35. Uchiyama K, Nakamura M, Kubota T, et al. 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.
36. Gilissen LP, Bierau J, Derijks LJ, et al. The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2005;22:605-611.
37. Hande S, Wilson-Rich N, Bousvaros A, et al. 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis. 2006;12:251-257.
38. 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. 2001;49:656-664.
39. Shah JA, Edwards CM, Probert CS. Should azathioprine and 5-aminosalicylates be coprescribed in inflammatory bowel disease?: an audit of adverse events and outcome. Eur J Gastroenterol Hepatol. 2008;20:169-173.
40. 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.
41. Gisbert JP, Gomollon F, Cara C, et al. Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci. 2007;52:1262-1269.
42. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis. 2008;14:542-549.