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TPMT Activity

TPMT Activity

Test Summary

TPMT Activity

  

Clinical Use

  • Identify patients at risk for toxicity from thiopurine drugs

  • Optimize thiopurine drug regimen or select alternative therapy

Clinical Background

Thiopurine drugs (azathioprine, 6-mercaptopurine [MP] and 6-thioguanine) are used to treat patients with lymphoblastic leukemia, rheumatic disease, chronic inflammatory diseases, or solid organ transplantation. These prodrugs are activated via a series of enzymatic reactions leading to production of thioguanine nucleotides (TGNs). TGNs are responsible for drug efficacy, but when in excess, cause myelosuppression and gastrointestinal toxicity.1 The level of TGNs produced is partially dependent on the activity of thiopurine methyltransferase (TPMT), an enzyme that reduces TGN production. Reduced TPMT activity results in increased TGN production and increased risk of toxicity when standard thiopurine doses are prescribed.1

TPMT activity is genetically controlled. Approximately 90% of individuals have normal TPMT activity (wild type), 10% have low activity (heterozygote/low metabolizer), and 0.3% have no or minimal detectable TPMT activity (homozygote deficient).1

Measurement of TPMT activity can predict thiopurine-induced myelosuppression, which can be life-threatening. Gisbert et al found that the risk of myelosuppression was 4.5-fold higher when TPMT activity was low vs normal in patients with inflammatory bowel disease (Crohn’s disease or ulcerative colitis).2 Similarly, in patients treated for chronic inflammatory disease (eg, systemic lupus erythematosus, progressive systemic sclerosis), myelosuppression has been shown to be more likely when TPMT activity was less than the upper reference level for heterozygotes.3

It follows that measurement of TMPT activity prior to treatment could be used to guide patient-specific thiopurine dosing, thereby minimizing the risk of drug toxicity. Selective dose reduction has been shown to mitigate toxicity while maintaining drug efficacy for patients with acute lymphoblastic leukemia,4 inflammatory bowel disease,5 or chronic inflammatory skin disease.6 Although thiopurine package inserts include recommendations that thiopurine dose reductions based on TPMT assessment may be required, specific dosing guidelines are not provided.7,8 However, clinical studies provide helpful information (see Interpretive Information).

Individuals Suitable for Testing

  • Patients being considered for thiopurine therapy

Method

  • Liquid chromatography, tandem mass spectrometry (LC/MS/MS)

   TPMT conversion of MP to 6-methylmercaptopurine (MMP)

   LC/MS/MS quantitation of MMP

   Volume of RBC calculated based on % hematocrit

   TPMT activity expressed as nmol/hr/mL of RBC

  • Analytical sensitivity: 0.7 nmol/hr/mL RBC

  • Analytical specificity: no significant interferences identified

  • Reportable range: 3–50 nmol/hr/mL RBC

  • Aliases: azathioprine toxicity; mercaptopurine toxicity

Interpretive Information

Risk of thiopurine toxicity is less with normal TPMT activity and higher with low or deficient activity. Reduction of drug dose by 33% to 50% should be considered for low-activity heterozygotes and by 90% to 95% for deficient-activity homozygotes.1,9,10 An alternative to thiopurine medication should be considered for patients with deficient TPMT activity.

TPMT activity can be inhibited by aminosalicylates such as mesalamine, olsalazine, and sulfasalazine, leading to potential toxicity.11 Aspirin and furosemide are also inhibitors of TPMT activity. In addition, recent blood transfusions can affect TPMT activity measurements so the TPMT Genotype assay (test code 37742Z), which is not affected, should be considered for patients who were recently transfused.

References

  1. McLeod HL, Krynetski EY, Relling M. et al. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood adult lymphoblastic leukemia. Leukemia. 2000;14:567-572.

  2. Gisbert JP, Nino P, Rodrigo L, et al. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol. 2006;101:2769-2776.

  3. Schedel J, Gödde A, Schütz E, et al. Impact of thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in patients with chronic inflammatory diseases. Ann NY Acad Sci. 2006;1069:477-491.

  4. Relling MV. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood. 2006;107:843-844.

  5. Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16:1743-1750.

  6. Meggitt S, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomized controlled trial. Lancet. 2006;367:839-846.

  7. Azasan® [package insert]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2003. Available at: http://www.salix.com/assets/pdf/prescribe_info/azasanpi.pdf. Accessed February 4, 2013.

  8. Purinethol® [package insert]. Sellersville, PA: Gate Pharmaceuticals; February 2007. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f9af557d-37bf-4078-888e-37c086dfc6e9. Accessed February 4, 2013.

  9. Hindorf U, LindQvist M, Hildebrand H, et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2006;24:331-342.

  10. van Asseldonk DP, Sanderson J, deBoer NKH, et al. Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease: proceedings of the first Thiopurine Task Force meeting. Dig Liver Dis. 2011;43:270-276.

  11. Lennard L. Clinical implications of thiopurine methyltransferase–optimization of drug dosage and potential drug interactions. Ther Drug Monit. 1998;20:527-531.
     

Content reviewed 04/2013
 
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