Expertos Invitados





UTILIDAD DE LA DETERMINACION DE LA ACTIVIDAD DE LA TIOPURINA METILTRANSFERASA PARA EL AJUSTE DE LA DOSIS DE AZATIOPRINA O MERCAPTOPURINA

(especial para SIIC © Derechos reservados)
La determinación de la actividad de la TPMT constituye una atractiva opción para individualizar la dosis de AZA o MP y prevenir el riesgo de efectos adversos.
Autor:
Javier p. Gisbert
Columnista Experto de SIIC

Institución:
Universidad Autónoma de Madrid (UAM)

Artículos publicados por Javier p. Gisbert
Recepción del artículo
22 de Febrero, 2010 		Aprobación
15 de Septiembre, 2010
Primera edición
10 de Noviembre, 2010 		Segunda edición, ampliada y corregida
7 de Junio, 2021

UTILIDAD DE LA DETERMINACION DE LA ACTIVIDAD DE LA TIOPURINA METILTRANSFERASA PARA EL AJUSTE DE LA DOSIS DE AZATIOPRINA O MERCAPTOPURINA

Resumen
La monitorización de la actividad de la tiopurina metiltransferasa (TPMT) se emplea para identificar a los pacientes tratados con azatioprina (AZA) y mercaptopurina (MP) que presentan mayor riesgo de mielotoxicidad. La actividad de la TPMT en la población general sigue una distribución trimodal, en la que aproximadamente el 11% de los individuos son heterocigotos y el 0.3% homocigotos para el alelo de baja actividad. Existen dos estrategias para identificar los pacientes con deficiencia de TPMT: la medición del fenotipo y del genotipo, con una elevada concordancia entre ambas técnicas. Se demostró una notable correlación entre el fenotipo o el genotipo de baja actividad de la TPMT y el riesgo de mielotoxicidad. Los pacientes con un genotipo homocigoto de alta actividad (o con actividad normal de la TPMT) deberían recibir dosis de inmunosupresores que hayan demostrado ser claramente eficaces. En aquellos enfermos con genotipo o fenotipo homocigoto de baja actividad de la TPMT se debería contraindicar el empleo de AZA/MP o, en todo caso, sería obligado administrar dosis muy reducidas de estos fármacos. En resumen, la determinación de la actividad de la TPMT constituye una atractiva opción para individualizar la dosis de AZA o MP y prevenir el riesgo de efectos adversos, aunque está por demostrarse si esta estrategia debe aplicarse rutinariamente en todos los pacientes. En cualquier caso, el fenotipo o el genotipo asociado con el déficit de TPMP explica únicamente un porcentaje de casos de mielotoxicidad, por lo que los controles analíticos periódicos deben seguir realizándose en estos pacientes a pesar de que la función de esta enzima sea normal.

Palabras clave
enfermedad de Crohn, colitis ulcerosa, enfermedad inflamatoria intestinal, azatioprina, mercaptopurina, tiopurina metiltransferasa, TPMT


Artículo completo
(castellano)
Extensión:  +/-8.46 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes

Role of Monitoring Thiopurine Methyltransferase (TPMT) Activity to Adjust Dosages of Azathioprine or Mercaptopurine

Abstract
Thiopurine methyltransferase (TPMT) activity monitoring has been used to identify those patients treated with azathioprine and mercaptopurine having a higher risk of myelotoxicity. A trimodal distribution of inheritance of TPMT activity has been described, with most of the patients (about 90%) being of the wild type, approximately 10% being heterozygous, and less than 0.5% being homozygous deficient. Several studies have demonstrated a high concordance between genotype and phenotype classification of TPMT activity. A high correlation between the low TPMT activity genotype/phenotype classification and the risk of myelotoxicity has been reported. High activity homozygous patients (with normal TPMT activity) should receive an effective (high) dose; homozygous patients (with low TPMT activity) should not receive azathioprine, although sometimes a very low dose (10%-15% of standard dose) could be administered. In summary, TPMT activity monitoring may be considered an encouraging strategy to choose, in a more individualized and safer way, the thiopurine dose. However, TPMT deficiency phenotype or genotype explains a variable proportion of myelotoxicity cases, but in no way explains all episodes of bone marrow suppression. Therefore, systematic blood controls should be done in azathioprine-treated patients despite TPMT phenotype/genotype being normal.

Key words
Crohn's disease, ulcerative colitis, inflammatory bowel disease, azathioprine, mercaptopurine, thiopurine methyltransferase, TPMT

Clasificación en siicsalud
Artículos originales > Expertos de Iberoamérica >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Bioquímica, Farmacología
Relacionadas: Diagnóstico por Laboratorio, Gastroenterología, Genética Humana, Hematología, Inmunología, Medicina Farmacéutica, Medicina Interna, Oncología, Reumatología



Comprar este artículo
Extensión: 8.46 páginas impresas en papel A4

file05.gif (1491 bytes) Artículos seleccionados para su compra



Enviar correspondencia a:
Javier P. Gisbert, 28669, Playa de Mojácar 29. Urb. Bonanza., Boadilla del Monte, España
Bibliografía del artículo


1. Gisbert JP, Gomollón F, Maté J, Pajares JM. Questions and answers on the role of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterol Hepatol 25:401-415, 2002.
2. Gisbert JP, Nino P, Cara C, Rodrigo L. Comparative effectiveness of azathioprine in Crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients. Aliment Pharmacol Ther 28:228-238, 2008.
3. Gisbert JP, Gomollón F, Maté J, Pajares JM. Individualized therapy with azathioprine or 6-mercaptopurine by monitoring thiopurine methyl-transferase (TPMT) activity. Rev Clin Esp 202:555-562, 2002.
4. Lennard L. TPMT in the treatment of Crohn's disease with azathioprine. Gut 51:143-146, 2002.
5. Dubinsky MC. Optimizing immunomodulator therapy for inflammatory bowel disease. Curr Gastroenterol Rep 5:506-511, 2003.
6. Seidman EG. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord 3(Suppl.1):S30-38, 2003.
7. Sandborn WJ. Pharmacogenomics and IBD: TPMT and thiopurines. Inflamm Bowel Dis 10(Suppl.1):S35-37, 2004.
8. Aberra FN, Lichtenstein GR. Review article: monitoring of immunomodulators in inflammatory bowel disease. Aliment Pharmacol Ther 21:307-319, 2005.
9. Al Hadithy AF, De Boer NK, Derijks LJ, Escher JC, Mulder CJ, Brouwers JR. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 37:282-297, 2005.
10. Coulthard S, Hogarth L. The thiopurines: An update. Invest New Drugs 2005.
11. Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol 20:1149-1157, 2005.
12. Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 118:705-713, 2000.
13. Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine--an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med 85:752-756, 1992.
14. Lowry PW, Franklin CL, Weaver AL, Pike MG, Mays DC, Tremaine WJ, et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut 49:665-670, 2001.
15. Bloomfeld RS, Onken JE. Mercaptopurine metabolite results in clinical gastroenterology practice. Aliment Pharmacol Ther 17:69-73, 2003.
16. Ho GT, Lees C, Satsangi J. Pharmacogenetics and inflammatory bowel disease: progress and prospects. Inflamm Bowel Dis 10:148-158, 2004.
17. Duley JA, Florin TH. Thiopurine therapies: problems, complexities, and progress with monitoring thioguanine nucleotides. Ther Drug Monit 27:647-654, 2005.
18. Lennard L, Brown CB, Fox M, Maddocks JL. Azathioprine metabolism in kidney transplant recipients. Br J Clin Pharmacol 18:693-700, 1984.
19. Lennard L. Assay of 6-thioinosinic acid and 6-thioguanine nucleotides, active metabolites of 6-mercaptopurine, in human red blood cells. J Chromatogr 423:169-178, 1987.
20. Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 7:1816-1823, 1989.
21. Cuffari C, Theoret Y, Latour S, Seidman G. 6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. Gut 39:401-406, 1996.
22. Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 48:642-646, 2001.
23. Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 343:1188-1190, 1994.
24. Bergan S, Rugstad HE, Bentdal O, Sodal G, Hartmann A, Leivestad T, et al. Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation. Transplantation 66:334-339, 1998.
25. Schutz E, Gummert J, Armstrong VW, Mohr FW, Oellerich M. Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. Eur J Clin Chem Clin Biochem 34:199-205, 1996.
26. Decaux G, Prospert F, Horsmans Y, Desager JP. Relationship between red cell mean corpuscular volume and 6-thioguanine nucleotides in patients treated with azathioprine. J Lab Clin Med 135:256-262, 2000.
27. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46:149-154, 1989.
28. Sandborn WJ, Faubion WA. Clinical pharmacology of inflammatory bowel disease therapies. Curr Gastroenterol Rep 2:440-445, 2000.
29. Dervieux T, Meyer G, Barham R, Matsutani M, Barry M, Boulieu R, et al. 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. Clin Chem 51:2074-2084, 2005.
30. Hindorf U, Lyrenas E, Nilsson A, Schmiegelow K. Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease. Scand J Gastroenterol 39:1105-1112, 2004.
31. Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2:410-417, 2004.
32. Derijks LJ, Gilissen LP, Engels LG, Bos LP, Bus PJ, Lohman JJ, et al. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. Ther Drug Monit 26:311-318, 2004.
33. Bergan S, Rugstad HE, Klemetsdal B, Giverhaug T, Bentdal O, Sodal G, et al. Possibilities for therapeutic drug monitoring of azathioprine: 6- thioguanine nucleotide concentrations and thiopurine methyltransferase activity in red blood cells. Ther Drug Monit 19:318-326, 1997.
34. Belaiche J, Desager JP, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol 36:71-76, 2001.
35. Paerregaard A, Schmiegelow K. Monitoring azathioprine metabolite levels and thiopurine methyl transferase (TPMT) activity in children with inflammatory bowel disease. Scand J Gastroenterol 37:371-372, 2002.
36. Gupta P, Gokhale R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 33:450-454, 2001.
37. Pettersson B, Almer S, Albertioni F, Soderhall S, Peterson C. Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy: possible role of concomitant methotrexate. Ther Drug Monit 24:351-358, 2002.
38. Reuther LO, Sonne J, Larsen NE, Larsen B, Christensen S, Rasmussen SN, et al. Pharmacological monitoring of azathioprine therapy. Scand J Gastroenterol 38:972-977, 2003.
39. Ansari A, Hassan C, Duley J, Marinaki A, Shobowale-Bakre EM, Seed P, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 16:1743-1750, 2002.
40. Lennard L. Therapeutic drug monitoring of antimetabolic cytotoxic drugs. Br J Clin Pharmacol 47:131-143, 1999.
41. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32:651-662, 1980.
42. Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 131:193-197, 1995.
43. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19:2293-2301, 2001.
44. Gisbert JP, Gomollón F, Cara C, Luna M, González-Lama Y, Pajares JM, et al. Thiopurine methyltransferase activity in inflammatory bowel disease. A study on 7046 Spanish patients. Med Clin (Barc) 125:281-285, 2005.
45. Gisbert JP, Gomollón F, Cara C, Luna M, González-Lama Y, Pajares JM, et al. Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci 52:1262-1269, 2007.
46. Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res 16:342-349, 1999.
47. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608-614, 1997.
48. Corominas H, Domenech M, González-Juan D, González-Suárez B, Díaz C, Pujol J, et al. Aplasia medular tras administración de azatioprina: papel del polimorfismo genético de la tiopurina metiltransferasa. Med Clin (Barc) 115:299-301, 2000.
49. Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129:716-718, 1988.
50. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001-2008, 1999.
51. Reuther LO, Sonne J, Larsen N, Dahlerup JF, Thomsen OO, Schmiegelow K. Thiopurine methyltransferase genotype distribution in patients with Crohn's disease. Aliment Pharmacol Ther 17:65-68, 2003.
52. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics 3:89-98, 2002.
53. Corominas H, Domenech M, González D, Díaz C, Roca M, García-González MA, et al. Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. Am J Gastroenterol 95:2313-2317, 2000.
54. Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 62:60-73, 1997.
55. Lindqvist M, Haglund S, Almer S, Peterson C, Taipalensu J, Hertervig E, et al. Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity. Pharmacogenetics 14:261-265, 2004.
56. Haglund S, Lindqvist M, Almer S, Peterson C, Taipalensuu J. Pyrosequencing of TPMT alleles in a general Swedish population and in patients with inflammatory bowel disease. Clin Chem 50:288-295, 2004.
57. Mascheretti S, Schreiber S. Genetic testing in crohn disease: utility in individualizing patient management. Am J Pharmacogenomics 5:213-222, 2005.
58. Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, 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 14:407-417, 2004.
59. Coulthard SA, Hall AG. Recent advances in the pharmacogenomics of thiopurine methyltransferase. Pharmacogenomics J 1:254-261, 2001.
60. Rossi AM, Bianchi M, Guarnieri C, Barale R, Pacifici GM. Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects. Eur J Clin Pharmacol 57:51-54, 2001.
61. Chrzanowska M, Kurzawski M, Drozdzik M, Mazik M, Oko A, Czekalski S. Thiopurine S-methyltransferase phenotype-genotype correlation in hemodialyzed patients. Pharmacol Rep 58:973-978, 2006.
62. Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics 2:148-159, 1992.
63. Vesell ES. Therapeutic lessons from pharmacogenetics. Ann Intern Med 126:653-655, 1997.
64. Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 118:1025-1030, 2000.
65. Chocair PR, Duley JA, Simmonds HA, Cameron JS. The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation 53:1051-1056, 1992.
66. Pazmino PA, Sladek SL, Weinshilboum RM. Thiol S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors. Clin Pharmacol Ther 28:356-367, 1980.
67. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 41:18-25, 1987.
68. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225-229, 1990.
69. McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 85:1897-1902, 1995.
70. Klemetsdal B, Straume B, Wist E, Aarbakke J. Identification of factors regulating thiopurine methyltransferase activity in a Norwegian population. Eur J Clin Pharmacol 44:147-152, 1993.
71. Pacifici GM, Romiti P, Giuliani L, Rane A. Thiopurine methyltransferase in humans: development and tissue distribution. Dev Pharmacol Ther 17:16-23, 1991.
72. Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 39:456-459, 1995.
73. Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum RM, et al. Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction. Clin Pharmacol Ther 62:464-475, 1997.
74. Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, et al. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 49:656-664, 2001.
75. Balis FM, Adamson PC. Application of pharmacogenetics to optimization of mercaptopurine dosing. J Natl Cancer Inst 91:1983-1985, 1999.
76. Tavadia SM, Mydlarski PR, Reis MD, Mittmann N, Pinkerton PH, Shear N, et al. Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol 42:628-632, 2000.
77. Schwab M, Schaeffeler W, Marx C, Zanger U, Aulitzky W, Eichelbaum M. Shortcoming in the diagnosis of TPMT deficiency in a patient with Crohn's disease using phenotyping only. Gastroenterology 121:500-501, 2001.
78. Cheung ST, Allan RN. Mistaken identity: misclassification of TPMT phenotype following blood transfusion. Eur J Gastroenterol Hepatol 15:1245-1247, 2003.
79. Lorenzen I, Brun C, Videbaek A. Treatment of immunologic diseases with cytostatics. Acta Med Scand 185:501-506, 1969.
80. Ginzler E, Sharon E, Diamond H, Kaplan D. Long-term maintenance therapy with azathioprine in systemic lupus erythematosus. Arthritis Rheum 18:27-34, 1975.
81. Mertens HG, Hertel G, Reuther P, Ricker K. Effect of immunosuppressive drugs (azathioprine). Ann N Y Acad Sci 377:691-699, 1981.
82. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 111:641-649, 1989.
83. Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34:1081-1085, 1993.
84. Ishioka S, Hiyama K, Sato H, Yamanishi Y, McLeod HL, Kumagai K, et al. Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. Intern Med 38:944-947, 1999.
85. Andersen JB, Szumlanski C, Weinshilboum RM, Schmiegelow K. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87:108-111, 1998.
86. Leipold G, Schutz E, Haas JP, Oellerich M. Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis. Arthritis Rheum 40:1896-1898, 1997.
87. Gummert JF, Schutz E, Oellerich M, Mohr FW, Dalichau H. Monitoring of TPMT in heart transplant recipients under immunosuppressive therapy with azathioprine. Artif Organs 19:918-920, 1995.
88. Ben Ari Z, Mehta A, Lennard L, Burroughs AK. Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis. J Hepatol 23:351-354, 1995.
89. Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LH, Van de Putte LB, Boerbooms AA. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 38:142-145, 1995.
90. Naughton MA, Battaglia E, O'Brien S, Walport MJ, Botto M. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology (Oxford) 38:640-644, 1999.
91. Schwab M, Schaffeler E, Marx C, Fischer C, Lang T, Behrens C, et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics 12:429-436, 2002.
92. Gearry RB, Barclay ML, Burt MJ, Collett JA, Chapman BA, Roberts RL, et al. Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Aliment Pharmacol Ther 18:395-400, 2003.
93. Sayani FA, Prosser C, Bailey RJ, Jacobs P, Fedorak RN. Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events. Can J Gastroenterol 19:147-151, 2005.
94. Kader HA, Wenner WJ Jr., Telega GW, Maller ES, Baldassano RN. Normal thiopurine methyltransferase levels do not eliminate 6- mercaptopurine or azathioprine toxicity in children with inflammatory bowel disease. J Clin Gastroenterol 30:409-413, 2000.
95. Gisbert JP, Luna M, Maté J, González-Guijarro L, Cara C, Pajares JM. Thiopurine methyltransferase activity and myelosuppression in inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Med Clin (Barc) 121:1-5, 2003.
96. Gisbert JP, Luna M, Maté J, González-Guijarro L, Cara C, Pajares JM. Choice of azathioprine or 6-mercaptopurine dose based on thiopurine methyltransferase (TPMT) activity to avoid myelosuppression. A prospective study. Hepatogastroenterology 53:399-404, 2006.
97. Sandborn WJ. Rational dosing of azathioprine and 6-mercaptopurine. Gut 48:591-592, 2001.
98. Gisbert JP, Nino P, Rodrigo L, Cara C, Guijarro LG. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol 101:2769-2776, 2006.
99. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119:985-989, 1991.
100. Lennard L, Lewis IJ, Michelagnoli M, Lilleyman JS. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies. Med Pediatr Oncol 29:252-255, 1997.
101. Kaskas BA, Louis E, Hindorf U, Schaeffeler E, Deflandre J, Graepler F, et al. Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. Gut 52:140-142, 2003.
102. Weyer N, Kroplin T, Fricke L, Iven H. Human thiopurine S-methyltransferase activity in uremia and after renal transplantation. Eur J Clin Pharmacol 57:129-136, 2001.
103. Mircheva J, Legendre C, Soria-Royer C, Thervet E, Beaune P, Kreis H. Monitoring of azathioprine-induced immunosuppression with thiopurine methyltransferase activity in kidney transplant recipients. Transplantation 60:639-642, 1995.
104. Keuzenkamp-Jansen CW, Leegwater PA, De Abreu RA, Lambooy MA, Bokkerink JP, Trijbels JM. Thiopurine methyltransferase: a review and a clinical pilot study. J Chromatogr B Biomed Appl 678:15-22, 1996.
105. Lowry PW, Szumlanski CL, Weinshilboum RM, Sandborn WJ. Balsalazide and azathiprine or 6-mercaptopurine: evidence for a potentially serious drug interaction. Gastroenterology 116:1505-1506, 1999.
106. Schwab M, Klotz U. Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet 40:723-751, 2001.
107. Gilissen LP, Bierau J, Derijks LJ, Bos LP, Hooymans PM, van Gennip A, et al. The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther 22:605-611, 2005.
108. Dewit O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn's disease. Aliment Pharmacol Ther 16:79-85, 2002.
109. Hande S, Wilson-Rich N, Bousvaros A, Zholudev A, Maurer R, Banks P, 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 12:251-257, 2006.
110. Campbell S, Ghosh S. Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy. Eur J Gastroenterol Hepatol 13:1297-1301, 2001.
111. Campbell S, Kingstone K, Ghosh S. Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low-dose azathioprine. Aliment Pharmacol Ther 16:389-398, 2002.
112. Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 122:904-915, 2002.
113. Menor C, Fueyo J, Escribano O, Pina MJ, Redondo P, Cara C, et al. Thiopurine methyltransferase activity in a spanish population sample: decrease of enzymatic activity in multiple sclerosis patients. Mult Scler 8:243-248, 2002.
114. Wright S, Sanders DS, Lobo AJ, Lennard L. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 53:1123-1128, 2004.
115. 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 36:390-395, 2003.
116. Dilger K, Schaeffeler E, Lukas M, Strauch U, Herfarth H, Muller R, et al. Monitoring of thiopurine methyltransferase activity in postsurgical patients with Crohn's disease during 1 year of treatment with azathioprine or mesalazine. Ther Drug Monit 29:1-5, 2007.
117. Regueiro M, Mardini H. Determination of thiopurine methyltransferase genotype or phenotype optimizes initial dosing of azathioprine for the treatment of Crohn's disease. J Clin Gastroenterol 35:240-244, 2002.
 
 
 
 
 
 
 
 
 
 
 
 
Está expresamente prohibida la redistribución y la redifusión de todo o parte de los contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin previo y expreso consentimiento de SIIC.
ua31618
Inicio/Home

Copyright siicsalud © 1997-2024 ISSN siicsalud: 1667-9008