Successful Azathioprine Treatment with Metabolite Monitoring in a Pediatric Inflammatory Bowel Disease Patient Homozygous for TPMT*3C
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6-thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18-year-old male diagnosed with Crohn’s disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity.
Abstract
Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6-thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18-year-old male diagnosed with Crohn’s disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity.
참고문헌 (26)
- Appell ML, "Nomenclature for alleles of the thiopurine methyltransferase gene", Pharmacogenet Genomics, 23, pp.242~248 (2013)
- Krynetski EY, "Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms", Pharmacogenetics, 6, pp.279~290 (1996)
- Tai HL, "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity", Proc Natl Acad Sci U S A, 94, pp.6444~6449 (1997)
- Tai HL, "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, 58, pp.694~702 (1996)
- Hindorf U, "Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease", Aliment Pharmacol Ther, 24, pp.331~342 (2006)
- Dewit O, "Thiopurine metabolism monitoring: implications in inflammatory bowel diseases", Eur J Clin Invest, 40, pp.1037~1047 (2010)
- Relling MV, "Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update", Clin Pharmacol Ther, 93, pp.324~325 (2013)
- Dervieux T, "Liquid chromatography-tandem mass spectrometry analysis of erythrocyte thiopurine nucleotides and effect of thiopurine methyltransferase gene variants on these metabolites in patients receiving azathioprine", 6-mercaptopurine therapy, 2005, pp.51, 2074~2084
- Dubinsky MC, "Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease", Gastroenterology, 118, pp.705~713 (2000)
- Cuffari C, "Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease", Clin Gastroenterol Hepatol, 2, pp.410~417 (2004)
- Kumagai K, "Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese", Pharmacogenetics, 11, pp.275~278 (2001)
- 김재학, "염증성 장질환 환자에서 Azathioprine", 6-Mercaptopurine 치료의 부작용: 빈도와 경과, 2008, pp.51(5), 291~297[DOI]
- Kim JH, "Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study", J Clin Gastroenterol, 44, pp.e242~e248 (2010)
- 이현주, "한국인 크론병 환자에서 Azathioprine", 6-Mercaptopurine 치료의 안전성과 유용성, 2009, pp.7(1), 22~31[DOI]
- Hindorf U, "Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease", Gut, 55, pp.1423~1431 (2006)
- Gisbert JP, "Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients", Am J Gastroenterol, 101, pp.2769~2776 (2006)
- Zelinkova Z, "Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression", Clin Gastroenterol Hepatol, 4, pp.44~49 (2006)
- Colombel JF, "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy", Gastroenterology, 118, pp.1025~1030 (2000)
- Takatsu N, "Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease", J Gastroenterol Hepatol, 24, pp.1258~1264 (2009)
- Ban H, "The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease", J Gastroenterol, 45, pp.1014~1021 (2010)
- Uchiyama K, "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, 2009, pp.44, 197~203
- Evans WE, "Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia", J Pediatr, 119, pp.985~989 (1991)
- Kaskas BA, "Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine", Gut, 52, pp.140~142 (2003)
- Grossman AB, "Increased dosing requirements for 6-mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger", Inflamm Bowel Dis, 14, pp.750~755 (2008)
- Nielsen OH, "Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine", Aliment Pharmacol Ther, 15, pp.1699~1708 (2001)
- Boonsrirat U, "Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism", Lupus, 17, pp.132~134 (2008)