Thiopurine metabolism monitoring: implications in inflammatory bowel diseases
Olivier Dewit,
Peter Starkel,
Xavier Roblin,
Olivier Dewit
St. Luc University Hospital, Catholic University of Louvain Brussels, Brussels, Belgium
Search for more papers by this authorPeter Starkel
St. Luc University Hospital, Catholic University of Louvain Brussels, Brussels, Belgium
Search for more papers by this authorOlivier Dewit,
Peter Starkel,
Xavier Roblin,
Olivier Dewit
St. Luc University Hospital, Catholic University of Louvain Brussels, Brussels, Belgium
Search for more papers by this authorPeter Starkel
St. Luc University Hospital, Catholic University of Louvain Brussels, Brussels, Belgium
Search for more papers by this authorOlivier Dewit, MD, Department of Gastroenterology, St. Luc University Hospital, Av. Hippocrate 10, 1200 Brussels, Belgium. Tel.: +32 2 764 2822; fax: 32 3 764 8927; e-mail: [email protected]
Abstract
Eur J Clin Invest 2010; 40 (11): 1037–1047
Background Thiopurines (TP) are widely used in the management of inflammatory bowel diseases. Side effects and inefficacy are a major concern as they lead to withdrawal of the drug.
Materials and Methods Tools investigating TP metabolism are useful to avoid inadequate cessation of TP therapy.
Results TP metabolism is complex and many enzymes are involved. Among them, Thiopurine methyl transferase is the only one routinely measured by pheno- or genotyping. A decreased TPMT activity results in a potential overdosing of TP drugs leading to myelotoxicity, whereas an ultra-high activity leads to TP ineffectiveness and overproduction of methylated compounds responsible for hepatotoxicity. TPMT determination prior to TP treatment results in an individual adapted dose. Xanthine oxidase/dehydrogenase (XOD), inosine triphosphate pyrophosphatase (ITPA) and glutathion-S-transferase (GST) are other promising enzyme targets that might help to explain TP efficacy or toxicity. ITPA and GST polymorphisms might potentially be related to some TP side effects, while a XOD inhibition by allopurinol could avoid TP-related hepatotoxicity.
Conclusions Utilization of thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is discussed, specifically, in case of thiopurine failure and recommendations are given about their interpretation and potential dose optimization. These enzymes and metabolites tests are complementary to the regular monitoring of blood cells count and liver tests which remains mandatory.
References
- 1 Bean RH. The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med J Aust 1962; 49: 592–3.
- 2 Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut 2005; 54: 237–41.
- 3 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: 331–42.
- 4 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 2004; 14: 407–17.
- 5 Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32: 651–62.
- 6 Derijks LJ, Wong DR. Pharmacogenetics of thiopurines in inflammatory bowel disease. Curr Pharm Des 2010; 16: 145–54.
- 7 Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE. 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 1997; 94: 6444–9.
- 8 Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 2004; 26: 186–91.
- 9 Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64: 753–67.
- 10 Lysaa RA, Giverhaug T, Wold HL, Aarbakke J. Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol 1996; 49: 393–6.
- 11 Xin HW, Fischer C, Schwab M, Klotz U. Thiopurine S-methyltransferase as a target for drug interactions. Eur J Clin Pharmacol 2005; 6: 395–8.
- 12 Oselin K, Anier K. Inhibition of human thiopurine S-methyltransferase by various nonsteroidal anti-inflammatory drugs in vitro: a mechanism for possible drug interactions. Drug Metab Dispos 2007; 35: 1452–4.
- 13 Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995; 39: 456–9.
- 14 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 2002; 16: 79–85.
- 15 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 2005; 22: 605–11.
- 16 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 2001; 49: 656–64.
- 17 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 2007; 29: 1–5.
- 18 Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, Van Kampen AH, Curvers WL et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 2006; 4: 44–9.
- 19 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 2006; 101: 2769–76.
- 20 Gisbert JP, Luna M, Mate J, Gonzalez-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 2006; 53: 399–404.
- 21 Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol 2008; 103: 1783–800.
- 22 Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004; 41(Pt 4): 294–302.
- 23 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 2002; 35: 240–4.
- 24 Gardiner SJ, Gearry RB, Begg EJ, Zhang M, Barclay ML. Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold. Clin Gastroenterol Hepatol 2008; 6: 654–60; quiz 604.
- 25 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 2003; 52: 140–2.
- 26 Ansari A, Hassan C, Duley J, Marinaki A, Shobowale-Bakre E-M, Seed P et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16: 1743–50.
- 27 Roberts RL, Gearry RB, Bland MV, Sies CW, George PM, Burt M et al. Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. Pharmacogenet Genomics 2008; 18: 434–8.
- 28 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 2004; 2: 410–7.
- 29 Ansari A, Arenas M, Greenfield SM, Morris D, Lindsay J, Gilshenan K et al. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28: 973–83.
- 30 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 2000; 118: 1025–30.
- 31 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 2001; 19: 2293–301.
- 32
Dewit O,
Moreels T,
Baert F,
Peeters H,
Reenaers C,
De Vos M
et al.
Impact of an extensive Thiopurine Methyltransferase genotyping in Inflammatory Bowel Disease patients who experienced myelosuppression during antipurine therapy.
Gastroenterology
2010; 138: S-671.
10.1016/S0016-5085(10)63088-0 Google Scholar
- 33 Oender K, Lanschuetzer C, Laimer M, Klausegger A, Paulweber B, Kofler B et al. Introducing a fast and simple PCR-RFLP analysis for the detection of mutant thiopurine methyltransferase alleles TPMT*3A and TPMT*3C. J Eur Acad Dermatol Venereol 2006; 20: 396–400.
- 34 Priest VL, Begg EJ, Gardiner SJ, Frampton CM, Gearry RB, Barclay ML et al. Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease. Pharmacoeconomics 2006; 24: 767–81.
- 35 Winter J, Walker A, Shapiro D, Gaffney D, Spooner RJ, Mills PR. Cost–effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20: 593–9.
- 36 Kitiyakara T, Hayat J, McIntyre AS. Cost–effectiveness of thiopurine methyltransferase genotype screening in IBD. Aliment Pharmacol Ther 2005; 21: 790–1; author reply 791–2.
- 37 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 2005; 19: 147–51.
- 38 Dubinsky MC, Reyes E, Ofman J, Chiou CF, Wade S, Sandborn WJ. A cost–effectiveness analysis of alternative disease management strategies in patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol 2005; 100: 2239–47.
- 39 Cara CJ, Pena AS, Sans M, Rodrigo L, Guerrero-Esteo M, Hinojosa J et al. Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice. Med Sci Monit 2004; 10: RA247–54.
- 40 Kashuba AD, Bertino JS Jr, Kearns GL, Leeder JS, James AW, Gotschall R et al. Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther 1998; 63: 540–51.
- 41 Wong DR, Derijks LJ, Den Dulk MO, Gemmeke EH, Hooymans PM. The role of xanthine oxidase in thiopurine metabolism: a case report. Ther Drug Monit 2007; 29: 845–8.
- 42 Relling MV, Lin JS, Ayers GD, Evans WE. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992; 52: 643–58.
- 43 Guerciolini R, Szumlanski C, Weinshilboum RM. Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther 1991; 50: 663–72.
- 44 Aklillu E, Carrillo JA, Makonnen E, Bertilsson L, Ingelman-Sundberg M. Xanthine oxidase activity is influenced by environmental factors in Ethiopians. Eur J Clin Pharmacol 2003; 59: 533–6.
- 45 Kudo M, Moteki T, Sasaki T, Konno Y, Ujiie S, Onose A et al. Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet Genomics 2008; 18: 243–51.
- 46 Hawwa AF, Millership JS, Collier PS, Vandenbroeck K, McCarthy A, Dempsey S et al. Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol 2008; 66: 517–28.
- 47 Smith MA, Marinaki AM, Arenas M, Shobowale-Bakre M, Lewis CM, Ansari A et al. Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Aliment Pharmacol Ther 2009; 30: 375–84.
- 48 Serre-Debeauvais F, Bayle F, Amirou M, Bechtel Y, Boujet C, Vialtel P et al. Hematotoxicity caused by azathioprine genetically determined and aggravated by xanthine oxidase deficiency in a patient following renal transplantation. Presse Med 1995; 24: 987–8.
- 49 Kennedy DT, Hayney MS, Lake KD. Azathioprine and allopurinol: the price of an avoidable drug interaction. Ann Pharmacother 1996; 30: 951–4.
- 50 Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007; 5: 209–14.
- 51 Leung M, Piatkov I, Rochester C, Boyages SC, Leong RWL. Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression. Internal Medicine Journal 2009; 39: 121–6.
- 52 Ansari A, Patel N, Sanderson J, O’Donohue J, Duley JA, Florin TH. 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: 640–7.
- 53 Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002; 5: 360–7.
- 54 Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14: 181–7.
- 55 Gearry RB, Roberts RL, Barclay ML, Kennedy MA. Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 2004; 14: 779–81.
- 56 Dubinsky MC, Feldman EJ, Abreu MT, Targan SR, Vasiliauskas EA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol 2003; 98: 1058–63.
- 57 Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298–303.
- 58 Allorge D, Hamdan R, Broly F, Libersa C, Colombel JF. ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut 2005; 54: 565.
- 59 Kurzawski M, Dziewanowski K, Lener A, Drozdzik M. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol 2009; 65: 533–40.
- 60 Schwab M, Klotz U. Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet 2001; 40: 723–51.
- 61 Eklund BI, Moberg M, Bergquist J, Mannervik B. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol 2006; 70: 747–54.
- 62 Stocco G, Martelossi S, Barabino A, Decorti G, Bartoli F, Montico M et al. Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 57–64.
- 63 Boulton-Jones JR, Pritchard K, Mahmoud AA. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 2000; 14: 1561–5.
- 64 Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott ID. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008; 27: 220–7.
- 65 Hindorf U, Johansson M, Eriksson A, Kvifors E, Almer SH. Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2009; 29: 654–61.
- 66 Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003; 111: 1133–45.
- 67 Neurath MF, Kiesslich R, Teichgraber U, Fischer C, Hofmann U, Eichelbaum M et al. 6-Thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease. Clin Gastroenterol Hepatol 2005; 3: 1007–14.
- 68 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 2000; 118: 705–13.
- 69 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 2001; 49: 665–70.
- 70 Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006; 130: 1047–53.
- 71 Reinshagen M, Schutz E, Armstrong VW, Behrens C, Von Tirpitz C, Stallmach A et al. 6-Thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active crohn disease: results from a randomized, controlled, open trial. Clin Chem 2007; 53: 1306–14.
- 72 Roblin X, Serre-Debeauvais F, Phelip JM, Faucheron JL, Hardy G, Chartier A et al. 6-Thioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine. Aliment Pharmacol Ther 2005; 21: 829–39.
- 73 Hindorf U, Lindqvist M, Peterson C, Soderkvist P, Strom M, Hjortswang H et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 2006; 55: 1423–31.
- 74 Sparrow MP, Irving PM, Hanauer SB. Optimizing conventional therapies for inflammatory bowel disease. Curr Gastroenterol Rep 2009; 11: 496–503.
- 75 Roblin X, Chartier A, Ducros V. Interaction between homocystein metabolism and TPMT activity in IBD patients under azathioprine. Gastroenterology 2006; 130(Suppl 2): A199.
- 76 Waljee AK, Joyce JC, Wang S, Saxena A, Hart M, Zhu J et al. Algorithms outperform metabolite tests in predicting response of patients with inflammatory bowel disease to thiopurines. Clin Gastroenterol Hepatol 2010; 8: 143–50.
- 77 Gupta P, Gokhale R, Kirschner B. 6-Mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001; 33: 450–54.
- 78 Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise therapy in patients with inflammatory bowel disease. Gut 2001; 48: 642–46.
- 79 Belaiche J, Desager JP, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol 2001; 36: 71–6.
- 80 Goldenberg BA, Rawsthorne P, Bernstein CN. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 2004; 99: 1744–48.
- 81 Achkar JP, Stevens T, Easley K, Brzezinski A, Seidner D, Lashner B. Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004; 10: 339–45.
