European Journal of Clinical Pharmacology

, Volume 64, Issue 8, pp 753–767 | Cite as

Clinical pharmacology and pharmacogenetics of thiopurines

  • Srikumar Sahasranaman
  • Danny Howard
  • Sandip RoyEmail author
Review Article


The thiopurine drugs—azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine—are widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease, and solid organ transplant rejection. However, thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life-threatening toxicity, most often myelosuppression. Thiopurine S-methyltransferase (TPMT; EC, an enzyme that catalyzes S-methylation of these drugs, exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity after receiving standard doses of thiopurine medications. This report reviews the recent advances in the knowledge of the mechanism of action as well as the molecular basis and interethnic variations of TPMT and inosine triphosphate pyrophosphatase (ITPase; EC, another enzyme implicated in thiopurine toxicity. In addition, an update on pharmacokinetics, metabolism, drug-drug interactions, safety, and tolerability of thiopurine drugs is provided.


Thiopurine Thiopurine methyltransferase Inosine triphosphate pyrophosphate Polymorphism Pharmacokinetics Drug interactions 



6-Guanosine triphosphate

6-MMP or 6-MeMP



6-Mercaptopurine, an immunomodulator


6-Thioguanine, the active AZA antimetabolite


6-Thioguanine nucleotide


6-Thiouric acid


Azathioprine, prodrug derivative of 6-MP


Complete blood count


Hypoxanthine phosphoribosyl transferase, an enzyme


Inflammatory bowel disease


Inosine monophosphate dehydrogenase


Inosine triphosphate pyrophosphatase


Mean corpuscular volume


Red blood cell


Thioinosic monophosphate, active metabolite


Thiopurine methyltransferase


White blood cell


  1. 1.
    Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN et al (1984) Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by cancer and leukemia group B. Blood 64(1):267–274PubMedGoogle Scholar
  2. 2.
    Veerman AJ, Hahlen K, Kamps WA, Van Leeuwen EF, De Vaan GA, Solbu G, Suciu S, Van Wering ER, Van der Does-Van der Berg A (1996) High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14(3):911–918PubMedGoogle Scholar
  3. 3.
    Lennon Y (1989) Adult acute leukemia. In: DiPiro JT, Talber RL, Hayes PE (eds) Pharmacotherapy: a pathophysiologic approach. Elsevier, New YorkGoogle Scholar
  4. 4.
    Anonymous (1993) Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 35(897):43–50Google Scholar
  5. 5.
    Holleb A, Fink D, Murphy G (1991) Clinical oncology. The American Cancer Scoiety, Atlanta, GAGoogle Scholar
  6. 6.
    Paton CM, Ekert H, Waters KD, Matthews RN, Toogood IR (1982) Treatment of acute myeloid leukaemia in children. Aust N Z J Med 12(2):143–146PubMedGoogle Scholar
  7. 7.
    Skeel R (1991) Handbook of cancer chemotherapy. Little, Brown and Company, BostonGoogle Scholar
  8. 8.
    Wollner N, Burchenal JH, Lieberman PH, Exelby P, D’Angio G, Murphy ML (1976) Non-Hodgkin’s lymphoma in children. A comparative study of two modalities of therapy. Cancer 37(1):123–134PubMedGoogle Scholar
  9. 9.
    Wollner N, Exelby PR, Lieberman PH (1979) Non-Hodgkin’s lymphoma in children: a progress report on the original patients treated with the LSA2-L2 protocol. Cancer 44(6):1990–1999PubMedGoogle Scholar
  10. 10.
    Pearson DC, May GR, Fick GH, Sutherland LR (1995) Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 123(2):132–142PubMedGoogle Scholar
  11. 11.
    Bean RH (1962) The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med J Aust 49(2):592–593PubMedGoogle Scholar
  12. 12.
    Kirk AP, Lennard-Jones JE (1982) Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J (Clin Res Ed) 284(6325):1291–1292CrossRefGoogle Scholar
  13. 13.
    Mahadevan U, Tremaine WJ, Johnson T, Pike MG, Mays DC, Lipsky JJ, Sandborn WJ (2000) Intravenous azathioprine in severe ulcerative colitis: a pilot study. Am J Gastroenterol 95(12):3463–3468PubMedGoogle Scholar
  14. 14.
    Ponticelli C, Tarantino A, Vegeto A (1999) Renal transplantation, past, present and future. J Nephrol 12(Suppl 2):S105–110PubMedGoogle Scholar
  15. 15.
    Pratt DS, Flavin DP, Kaplan MM (1996) The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 110(1):271–274PubMedGoogle Scholar
  16. 16.
    Heurkens AH, Westedt ML, Breedveld FC (1991) Prednisone plus azathioprine treatment in patients with rheumatoid arthritis complicated by vasculitis. Arch Intern Med 151(11):2249–2254PubMedGoogle Scholar
  17. 17.
    Abu-Shakra M, Shoenfeld Y (2001) Azathioprine therapy for patients with systemic lupus erythematosus. Lupus 10(3):152–153PubMedGoogle Scholar
  18. 18.
    Silvis NG, Levine N (1999) Pulse dosing of thioguanine in recalcitrant psoriasis. Arch Dermatol 135(4):433–437PubMedGoogle Scholar
  19. 19.
    Murphy LA, Atherton DJ (2003) Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency. Pediatr Dermatol 20(6):531–534PubMedGoogle Scholar
  20. 20.
    Teml A, Schaeffeler E, Herrlinger KR, Klotz U, Schwab M (2007) Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet 46(3):187–208PubMedGoogle Scholar
  21. 21.
    Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS (1980) Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 302(18):981–987PubMedGoogle Scholar
  22. 22.
    Derijks LJ, Gilissen LP, Hooymans PM, Hommes DW (2006) Review article: thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther 24(5):715–729PubMedGoogle Scholar
  23. 23.
    Hanauer SB, Sandborn W (2001) Management of Crohn’s disease in adults. Am J Gastroenterol 96(3):635–643PubMedGoogle Scholar
  24. 24.
    Kornbluth A, Sachar DB (1997) Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 92(2):204–211PubMedGoogle Scholar
  25. 25.
    Lennard L (1992) The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 43(4):329–339PubMedGoogle Scholar
  26. 26.
    Swann PF, Waters TR, Moulton DC, Xu YZ, Zheng Q, Edwards M, Mace R (1996) Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273(5278):1109–1111PubMedGoogle Scholar
  27. 27.
    Inamochi H, Higashigawa M, Shimono Y, Nagata T, Cao DC, Mao XY, M’Soka T, Hori H, Kawasaki H, Sakurai M (1999) Delayed cytotoxicity of 6-mercaptopurine is compatible with mitotic death caused by DNA damage due to incorporation of 6-thioguanine into DNA as 6-thioguanine nucleotide. J Exp Clin Cancer Res 18(3):417–424PubMedGoogle Scholar
  28. 28.
    Elion GB, Callahan S, Rundles RW, Hitchings GH (1963) Relationship between metabolic fates and antitumor activities of thiopurines. Cancer Res 23:1207–1217PubMedGoogle Scholar
  29. 29.
    Hamilton L, Elion GB (1954) The fate of 6-mercaptopurine in man. Ann N Y Acad Sci 60(2):304–314PubMedCrossRefGoogle Scholar
  30. 30.
    Allan PW, Bennett LL Jr (1971) 6-Methylthioguanylic acid, a metabolite of 6-thioguanine. Biochem Pharmacol 20(4):847–852PubMedGoogle Scholar
  31. 31.
    Tay BS, Lilley RM, Murray AW, Atkinson MR (1969) Inhibition of phosphoribosyl pyrophosphate amidotransferase from Ehrlich ascites-tumour cells by thiopurine nucleotides. Biochem Pharmacol 18(4):936–938PubMedGoogle Scholar
  32. 32.
    Elion GB (1989) The purine path to chemotherapy. Science 244(4900):41–47PubMedGoogle Scholar
  33. 33.
    Erb N, Harms DO, Janka-Schaub G (1998) Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 42(4):266–272PubMedGoogle Scholar
  34. 34.
    Thomas CW, Myhre GM, Tschumper R, Sreekumar R, Jelinek D, McKean DJ, Lipsky JJ, Sandborn WJ, Egan LJ (2005) Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines. J Pharmacol Exp Ther 312(2):537–545PubMedGoogle Scholar
  35. 35.
    Boirivant M, Marini M, Di Felice G, Pronio AM, Montesani C, Tersigni R, Strober W (1999) Lamina propria T cells in Crohn’s disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 116(3):557–565PubMedGoogle Scholar
  36. 36.
    Breese E, Braegger CP, Corrigan CJ, Walker-Smith JA, MacDonald TT (1993) Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology 78(1):127–131PubMedGoogle Scholar
  37. 37.
    Plevy SE, Landers CJ, Prehn J, Carramanzana NM, Deem RL, Shealy D, Targan SR (1997) A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 159(12):6276–6282PubMedGoogle Scholar
  38. 38.
    Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, Mudter J, Hildner K, Bartsch B, Holtmann M, Blumberg R, Walczak H, Iven H, Galle PR, Ahmadian MR, Neurath MF (2003) CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111(8):1133–1145PubMedGoogle Scholar
  39. 39.
    Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P (2001) Antineoplastic agents. In: Hardman JG, Limbird LE, Goodman Gillman A (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 10th ed. McGraw-Hill, New YorkGoogle Scholar
  40. 40.
    Sandborn WJ, Tremaine WJ, Wolf DC, Targan SR, Sninsky CA, Sutherland LR, Hanauer SB, McDonald JW, Feagan BG, Fedorak RN, Isaacs KL, Pike MG, Mays DC, Lipsky JJ, Gordon S, Kleoudis CS, Murdock RH Jr (1999) Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn’s disease. North American Azathioprine Study Group. Gastroenterology 117(3):527–535PubMedGoogle Scholar
  41. 41.
    Elion GB (1969) Actions of purine analogs: enzyme specificity studies as a basis for interpretation and design. Cancer Res 29(12):2448–2453PubMedGoogle Scholar
  42. 42.
    Elion GB (1967) Symposium on immunosuppressive drugs. Biochemistry and pharmacology of purine analogues. Fed Proc 26(3):898–904PubMedGoogle Scholar
  43. 43.
    Weinshilboum RM, Raymond FA, Pazmino PA (1978) Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clin Chim Acta 85(3):323–333PubMedGoogle Scholar
  44. 44.
    Berns A, Rubenfeld S, Rymzo WT Jr, Calabro JJ (1972) Hazard of combining allopurinol and thiopurine. N Engl J Med 286(13):730–731PubMedGoogle Scholar
  45. 45.
    Zimm S, Collins JM, O’Neill D, Chabner BA, Poplack DG (1983) Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 34(6):810–817PubMedGoogle Scholar
  46. 46.
    Zimm S, Grygiel JJ, Strong JM, Monks TJ, Poplack DG (1984) Identification of 6-mercaptopurine riboside in patients receiving 6-mercaptopurine as a prolonged intravenous infusion. Biochem Pharmacol 33(24):4089–4092PubMedGoogle Scholar
  47. 47.
    Krenitsky TA, Neil SM, Elion GB, Hitchings GH (1972) A comparison of the specificities of xanthine oxidase and aldehyde oxidase. Arch Biochem Biophys 150(2):585–599PubMedGoogle Scholar
  48. 48.
    Kitchen BJ, Balis FM, Poplack DG, O’Brien M, Craig CE, Adamson PC (1997) A pediatric phase I trial and pharmacokinetic study of thioguanine administered by continuous i.v. infusion. Clin Cancer Res 3(5):713–717PubMedGoogle Scholar
  49. 49.
    Konits PH, Egorin MJ, Van Echo DA, Aisner J, Andrews PA, May ME, Bachur NR, Wiernik PH (1982) Phase II evaluation and plasma pharmacokinetics of high-dose intravenous 6-thioguanine in patients with colorectal carcinoma. Cancer Chemother Pharmacol 8(2):199–203PubMedGoogle Scholar
  50. 50.
    Bronk JR, Lister N, Shaw MI (1988) Transport and metabolism of 6-thioguanine and 6-mercaptopurine in mouse small intestine. Clin Sci (Lond) 74(6):629–638Google Scholar
  51. 51.
    Kitchen BJ, Moser A, Lowe E, Balis FM, Widemann B, Anderson L, Strong J, Blaney SM, Berg SL, O’Brien M, Adamson PC (1999) Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine. J Pharmacol Exp Ther 291(2):870–874PubMedGoogle Scholar
  52. 52.
    Chan GL, Erdmann GR, Gruber SA, Matas AJ, Canafax DM (1990) Azathioprine metabolism: pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients. J Clin Pharmacol 30(4):358–363PubMedGoogle Scholar
  53. 53.
    Arnott ID, Watts D, Satsangi J (2003) Azathioprine and anti-TNF alpha therapies in Crohn’s disease: a review of pharmacology, clinical efficacy and safety. Pharmacol Res 47(1):1–10PubMedGoogle Scholar
  54. 54.
    Lancaster DL, Patel N, Lennard L, Lilleyman JS (2001) 6-Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations. Br J Clin Pharmacol 51(6):531–539PubMedGoogle Scholar
  55. 55.
    Bell BA, Brockway GN, Shuster JJ, Erdmann G, Sterikoff S, Bostrom B, Camitta BM (2004) A comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children’s Oncology Group). Pediatr Blood Cancer 43(2):105–109PubMedGoogle Scholar
  56. 56.
    Lindqvist M, Hindorf U, Almer S, Soderkvist P, Strom M, Hjortswang H, Peterson C (2006) No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease. Nucleosides Nucleotides Nucleic Acids 25(9–11):1033–1037PubMedGoogle Scholar
  57. 57.
    Mori S, Ohtsuki S, Takanaga H, Kikkawa T, Kang YS, Terasaki T (2004) Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem 90(4):931–941PubMedGoogle Scholar
  58. 58.
    Gardiner SJ, Gearry RB, Roberts RL, Zhang M, Barclay ML, Begg EJ (2006) Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs. Br J Clin Pharmacol 62(4):453–456PubMedGoogle Scholar
  59. 59.
    Moretti ME, Verjee Z, Ito S, Koren G (2006) Breast-feeding during maternal use of azathioprine. Ann Pharmacother 40(12):2269–2272PubMedGoogle Scholar
  60. 60.
    Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119(6):985–989PubMedGoogle Scholar
  61. 61.
    Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336(8709):225–229PubMedGoogle Scholar
  62. 62.
    McLeod HL, Miller DR, Evans WE (1993) Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 341(8853):1151PubMedGoogle Scholar
  63. 63.
    Chocair PR, Duley JA, Simmonds HA, Cameron JS (1992) The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation 53(5):1051–1056PubMedGoogle Scholar
  64. 64.
    Soria-Royer C, Legendre C, Mircheva J, Premel S, Beaune P, Kreis H (1993) Thiopurine-methyl-transferase activity to assess azathioprine myelotoxicity in renal transplant recipients. Lancet 341(8860):1593–1594PubMedGoogle Scholar
  65. 65.
    Lennard L, Lilleyman JS (1989) Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 7(12):1816–1823PubMedGoogle Scholar
  66. 66.
    Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, Seidman EG (2000) Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 118(4):705–713PubMedGoogle Scholar
  67. 67.
    Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32(5):651–662PubMedGoogle Scholar
  68. 68.
    Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, Relling MV, Evans WE (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6(4):279–290PubMedGoogle Scholar
  69. 69.
    McLeod HL, Krynetski EY, Relling MV, Evans WE (2000) Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14(4):567–572PubMedGoogle Scholar
  70. 70.
    McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE (1994) Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 55(1):15–20PubMedGoogle Scholar
  71. 71.
    Thervet E, Anglicheau D, Toledano N, Houllier AM, Noel LH, Kreis H, Beaune P, Legendre C (2001) Long-term results of TMPT activity monitoring in azathioprine-treated renal allograft recipients. J Am Soc Nephrol 12(1):170–176PubMedGoogle Scholar
  72. 72.
    Mahadevan U, Sandborn W (2004) Clinical pharmacology of inflammatory bowel disease. In: Sartor RB, Sandborn WJ (eds) Kirsner’s inflammatory bowel diseases, 6th ed. Saunders, PhiladelphiaGoogle Scholar
  73. 73.
    Weinshilboum R (2001) Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 29(4 Pt 2):601–605PubMedGoogle Scholar
  74. 74.
    Weinshilboum RM, Otterness DM, Szumlanski CL (1999) Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 39:19–52PubMedGoogle Scholar
  75. 75.
    Woodson LC, Ames MM, Selassie CD, Hansch C, Weinshilboum RM (1983) Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 24(3):471–478PubMedGoogle Scholar
  76. 76.
    Woodson LC, Weinshilboum RM (1983) Human kidney thiopurine methyltransferase. Purification and biochemical properties. Biochem Pharmacol 32(5):819–826PubMedGoogle Scholar
  77. 77.
    Krynetski EY, Evans WE (1999) Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res 16(3):342–349PubMedGoogle Scholar
  78. 78.
    Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, Iven H, Schmiegelow K, Branum E, O’Brien J, Weinshilboum R (1997) Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 62(1):60–73PubMedGoogle Scholar
  79. 79.
    Otterness DM, Szumlanski CL, Wood TC, Weinshilboum RM (1998) Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J Clin Invest 101(5):1036–1044PubMedGoogle Scholar
  80. 80.
    Spire-Vayron de la Moureyre C, Debuysere H, Sabbagh N, Marez D, Vinner E, Chevalier ED, Lo Guidice JM, Broly F (1998) Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat 12(3):177–185PubMedGoogle Scholar
  81. 81.
    Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE (1997) 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 USA 94(12):6444–6449PubMedGoogle Scholar
  82. 82.
    Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, Evans WE (1996) 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(4):694–702PubMedGoogle Scholar
  83. 83.
    Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126(8):608–614PubMedGoogle Scholar
  84. 84.
    Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE (1995) A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 92(4):949–953PubMedGoogle Scholar
  85. 85.
    Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, McLeod HL (1999) The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 9(1):37–42PubMedGoogle Scholar
  86. 86.
    McLeod HL, Pritchard SC, Githang’a J, Indalo A, Ameyaw MM, Powrie RH, Booth L, Collie-Duguid ES (1999) Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan individuals. Pharmacogenetics 9(6):773–776PubMedGoogle Scholar
  87. 87.
    Tai HL, Fessing MY, Bonten EJ, Yanishevsky Y, d’Azzo A, Krynetski EY, Evans WE (1999) Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C. Pharmacogenetics 9(5):641–650PubMedGoogle Scholar
  88. 88.
    Loennechen T, Yates CR, Fessing MY, Relling MV, Krynetski EY, Evans WE (1998) Isolation of a human thiopurine S-methyltransferase (TPMT) complementary DNA with a single nucleotide transition A719G (TPMT*3C) and its association with loss of TPMT protein and catalytic activity in humans. Clin Pharmacol Ther 64(1):46–51PubMedGoogle Scholar
  89. 89.
    Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE (1999) Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 8(2):371–376PubMedGoogle Scholar
  90. 90.
    Hamdan-Khalil R, Allorge D, Lo-Guidice JM, Cauffiez C, Chevalier D, Spire C, Houdret N, Libersa C, Lhermitte M, Colombel JF, Gala JL, Broly F (2003) In vitro characterization of four novel non-functional variants of the thiopurine S-methyltransferase. Biochem Biophys Res Commun 309(4):1005–1010PubMedGoogle Scholar
  91. 91.
    Lindqvist M, Haglund S, Almer S, Peterson C, Taipalensu J, Hertervig E, Lyrenas E, Soderkvist P (2004) Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity. Pharmacogenetics 14(4):261–265PubMedGoogle Scholar
  92. 92.
    Alves S, Amorim A, Ferreira F, Prata MJ (2001) Influence of the variable number of tandem repeats located in the promoter region of the thiopurine methyltransferase gene on enzymatic activity. Clin Pharmacol Ther 70(2):165–174PubMedGoogle Scholar
  93. 93.
    Alves S, Ferreira F, Prata MJ, Amorim A (2000) Characterization of three new VNTR alleles in the promoter region of the TPMT gene. Hum Mutat 15(1):121PubMedGoogle Scholar
  94. 94.
    Spire-Vayron de la Moureyre C, Debuysere H, Fazio F, Sergent E, Bernard C, Sabbagh N, Marez D, Lo Guidice JM, D’Halluin JC, Broly F (1999) Characterization of a variable number tandem repeat region in the thiopurine S-methyltransferase gene promoter. Pharmacogenetics 9(2):189–198PubMedGoogle Scholar
  95. 95.
    Yan L, Zhang S, Eiff B, Szumlanski CL, Powers M, O’Brien JF, Weinshilboum RM (2000) Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clin Pharmacol Ther 68(2):210–219PubMedGoogle Scholar
  96. 96.
    Marinaki AM, Arenas M, Khan ZH, Lewis CM, Shobowale-Bakre el M, Escuredo E, Fairbanks LD, Mayberry JF, Wicks AC, Ansari A, Sanderson J, Duley JA (2003) Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians. Pharmacogenetics 13(2):97–105PubMedGoogle Scholar
  97. 97.
    Gate Pharmaceuticals (2007) Purinethol (mercaptopurine) prescribing information. Accessed 8 March 2008
  98. 98.
    Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 8(2):367–370Google Scholar
  99. 99.
    Ganiere-Monteil C, Medard Y, Lejus C, Bruneau B, Pineau A, Fenneteau O, Bourin M, Jacqz-Aigrain E (2004) Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol 60(2):89–96Google Scholar
  100. 100.
    Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, Zanger UM, Schwab M (2004) Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14(7):407–417Google Scholar
  101. 101.
    Kurzawski M, Gawronska-Szklarz B, Drozdzik M (2004) Frequency distribution of thiopurine S-methyltransferase alleles in a polish population. Ther Drug Monit 26(5):541–545Google Scholar
  102. 102.
    Haglund S, Lindqvist M, Almer S, Peterson C, Taipalensuu J (2004) Pyrosequencing of TPMT alleles in a general Swedish population and in patients with inflammatory bowel disease. Clin Chem 50(2):288–295Google Scholar
  103. 103.
    Loennechen T, Utsi E, Hartz I, Lysaa R, Kildalsen H, Aarbakke J (2001) Detection of one single mutation predicts thiopurine S-methyltransferase activity in a population of Saami in northern Norway. Clin Pharmacol Ther 70(2):183–188Google Scholar
  104. 104.
    Indjova D, Atanasova S, Shipkova M, Armstrong VW, Oellerich M, Svinarov D (2003) Phenotypic and genotypic analysis of thiopurine s-methyltransferase polymorphism in the bulgarian population. Ther Drug Monit 25(5):631–636PubMedGoogle Scholar
  105. 105.
    Larovere LE, de Kremer RD, Lambooy LH, De Abreu RA (2003) Genetic polymorphism of thiopurine S-methyltransferase in Argentina. Ann Clin Biochem 40(Pt 4):388–393PubMedGoogle Scholar
  106. 106.
    Zhang JP, Guan YY, Xu AL, Zhou SF, Wu JH, Wei H, Huang M (2004) Gene mutation of thiopurine S-methyltransferase in Uygur Chinese. Eur J Clin Pharmacol 60 (1): 1-3Google Scholar
  107. 107.
    Kumagai K, Hiyama K, Ishioka S, Sato H, Yamanishi Y, McLeod HL, Konishi F, Maeda H, Yamakido M (2001) Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics 11(3):275–278Google Scholar
  108. 108.
    Srimartpirom S, Tassaneeyakul W, Kukongviriyapan V, Tassaneeyakul W (2004) Thiopurine S-methyltransferase genetic polymorphism in the Thai population. Br J Clin Pharmacol 58(1):66-70Google Scholar
  109. 109.
    Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, Liang DC (2002) Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics 12(3):191–195PubMedGoogle Scholar
  110. 110.
    Boson WL, Romano-Silva MA, Correa H, Falcao RP, Teixeira-Vidigal PV, De Marco L (2003) Thiopurine methyltransferase polymorphisms in a Brazilian population. Pharmacogenomics J 3(3):178–182Google Scholar
  111. 111.
    Zhang JP, Guan YY, Wu JH, Xu AL, Zhou S, Huang M (2004) Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children: a comparison of Han and Yao ethnic groups. Br J Clin Pharmacol 58(2):163–168Google Scholar
  112. 112.
    Isaza C, Henao J, Lopez AM, Cacabelos R (2003) Allelic variants of the thiopurine methyltransferase (TPMT) gene in the Colombian population. Methods Find Exp Clin Pharmacol 25(6):423–429Google Scholar
  113. 113.
    Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed MS, Mizugaki M (2003) Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Br J Clin Pharmacol 55(6):560–569Google Scholar
  114. 114.
    Rossi AM, Bianchi M, Guarnieri C, Barale R, Pacifici GM (2001) Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects. Eur J Clin Pharmacol 57(1):51–54PubMedGoogle Scholar
  115. 115.
    McLeod HL, Siva C (2002) The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics 3(1):89–98PubMedGoogle Scholar
  116. 116.
    Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91(23):2001–2008PubMedGoogle Scholar
  117. 117.
    Kham SK, Tan PL, Tay AH, Heng CK, Yeoh AE, Quah TC (2002) Thiopurine methyltransferase polymorphisms in a multiracial Asian population and children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 24(5):353–359PubMedGoogle Scholar
  118. 118.
    Klemetsdal B, Tollefsen E, Loennechen T, Johnsen K, Utsi E, Gisholt K, Wist E, Aarbakke J (1992) Interethnic difference in thiopurine methyltransferase activity. Clin Pharmacol Ther 51(1):24–31PubMedGoogle Scholar
  119. 119.
    Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26(2):186–191PubMedGoogle Scholar
  120. 120.
    Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, Kalwinsky D, Keller F, Khatib Z, Margolin J, Murray J, Quinn J, Ravindranath Y, Ritchey K, Roberts W, Rogers ZR, Schiff D, Steuber C, Tucci F, Kornegay N, Krynetski EY, Relling MV (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301PubMedGoogle Scholar
  121. 121.
    Langley PG, Underhill J, Tredger JM, Norris S, McFarlane IG (2002) Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. J Hepatol 37(4):441–447PubMedGoogle Scholar
  122. 122.
    Marinaki AM, Sumi S, Arenas M, Fairbanks L, Harihara S, Shimizu K, Ueta A, Duley JA (2004) Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population. Nucleosides Nucleotides Nucleic Acids 23(8–9):1399–1401PubMedGoogle Scholar
  123. 123.
    Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM, Shobowale-Bakre el M, Escuredo E, Fairbanks LD, Sanderson JD (2004) Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14(3):181–187PubMedGoogle Scholar
  124. 124.
    Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, Thein SL, Ansari A, Sanderson J, De Abreu RA, Simmonds HA, Duley JA (2002) Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 111(4–5):360–367PubMedGoogle Scholar
  125. 125.
    Gearry RB, Roberts RL, Barclay ML, Kennedy MA (2004) Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 14(11):779–781PubMedGoogle Scholar
  126. 126.
    Marsh S, King CR, Ahluwalia R, McLeod HL (2004) Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet 49(10):579–581PubMedGoogle Scholar
  127. 127.
    Szumlanski CL, Weinshilboum RM (1995) Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 39(4):456–459PubMedGoogle Scholar
  128. 128.
    Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum RM, Nierenberg DW (1997) Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction. Clin Pharmacol Ther 62(4):464–475PubMedGoogle Scholar
  129. 129.
    Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ (2001) Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 49(5):656–664PubMedGoogle Scholar
  130. 130.
    Gilissen LP, Bierau J, Derijks LJ, Bos LP, Hooymans PM, van Gennip A, Stockbrugger RW, Engels LG (2005) The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther 22(7):605–611PubMedGoogle Scholar
  131. 131.
    Roblin X, Serre-Debeauvais F, Phelip JM, Bessard G, Bonaz B (2003) Drug interaction between infliximab and azathioprine in patients with Crohn’s disease. Aliment Pharmacol Ther 18(9):917–925PubMedGoogle Scholar
  132. 132.
    Martin LA, Mehta SD (2003) Diminished anticoagulant effects of warfarin with concomitant mercaptopurine therapy. Pharmacotherapy 23(2):260–264PubMedGoogle Scholar
  133. 133.
    Singleton JD, Conyers L (1992) Warfarin and azathioprine: an important drug interaction. Am J Med 92(2):217PubMedGoogle Scholar
  134. 134.
    Shepherd PC, Fooks J, Gray R, Allan NC (1991) Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non-cirrhotic portal hypertension. Results from MRC CML. II. Trial comparing busulphan with busulphan and thioguanine. Br J Haematol 79(2):185–192PubMedGoogle Scholar
  135. 135.
    Rosenbaum EH, Cohen RA, Glatstein HR (1966) Vaccination of a patient receiving immunosuppressive therapy for lymphosarcoma. JAMA 198(7):737–740PubMedGoogle Scholar
  136. 136.
    Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH (1993) Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors. Transplantation 56(3):585–589PubMedGoogle Scholar
  137. 137.
    Gossmann J, Thurmann P, Bachmann T, Weller S, Kachel HG, Schoeppe W, Scheuermann EH (1996) Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients. Kidney Int 50(3):973–978PubMedGoogle Scholar
  138. 138.
    Lysaa RA, Giverhaug T, Wold HL, Aarbakke J (1996) Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol 49(5):393–396PubMedGoogle Scholar
  139. 139.
    Xin HW, Fischer C, Schwab M, Klotz U (2005) Thiopurine S-methyltransferase as a target for drug interactions. Eur J Clin Pharmacol 61(5–6):395–398PubMedGoogle Scholar
  140. 140.
    Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI (1989) 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 111(8):641–649PubMedGoogle Scholar
  141. 141.
    Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C (2004) Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease.Cochrane Database Syst Rev. DOI  10.1002/14651858.CD000545
  142. 142.
    Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE (1993) Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34(8):1081–1085PubMedGoogle Scholar
  143. 143.
    Colonna T, Korelitz BI (1994) The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol 89(3):362–366PubMedGoogle Scholar
  144. 144.
    Kirschner BS (1998) Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 115(4):813–821PubMedGoogle Scholar
  145. 145.
    Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA (2002) 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 122(4):904–915PubMedGoogle Scholar
  146. 146.
    Dubinsky MC (2003) Optimizing immunomodulator therapy for inflammatory bowel disease. Curr Gastroenterol Rep 5(6):506–511PubMedGoogle Scholar
  147. 147.
    Herrlinger KR, Schwab M, Fellermann K, Stange EF (2004) 6-thioguanine—buried alive? Gastroenterology 126(3):940–941, author reply 941–942PubMedGoogle Scholar
  148. 148.
    Sanderson J, Ansari A, Marinaki T, Duley J (2004) Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 41(Pt 4):294–302PubMedGoogle Scholar
  149. 149.
    Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL (2001) Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 121(5):1080–1087PubMedGoogle Scholar
  150. 150.
    Loftus EV Jr, Tremaine WJ, Habermann TM, Harmsen WS, Zinsmeister AR, Sandborn WJ (2000) Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol 95(9):2308–2312PubMedGoogle Scholar
  151. 151.
    Dayharsh GA, Loftus EV Jr, Sandborn WJ, Tremaine WJ, Zinsmeister AR, Witzig TE, Macon WR, Burgart LJ (2002) Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 122(1):72–77PubMedGoogle Scholar
  152. 152.
    Stork LC, Erdmaru G, Adamson P, Bostrom B, Matloub YH, Holcenberg I, Blake M, Kelleher JF, Masterson M, Ettinger RS, Sacher HN, Gaynon PS (1998) Oral 6-thioguanine (TG) causes relatively mild and reversible hepatic venoocclusive disease (VOD). J Pediatr Hematol/Oncol 20(4):400Google Scholar
  153. 153.
    Jacobs SS, Stork LC, Bostrom BC, Hutchinson R, Holcenberg J, Reaman GH, Erdmann G, Franklin J, Neglia JP, Steinberg SM, Balis FM, Adamson PC (2006) Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative children’s oncology group/national cancer institute pilot trial (CCG-1942). Pediatr Blood Cancer 49(3):250–255Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Srikumar Sahasranaman
    • 1
  • Danny Howard
    • 1
  • Sandip Roy
    • 1
    Email author
  1. 1.Drug Metabolism and PharmacokineticsNovartis Pharmaceuticals CorporationEast HanoverUSA

Personalised recommendations