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Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients

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Abstract

We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 ± 6 U/mL, but differed depending on the disease (P < .001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0–13.7) in 11.9%; or high (≥13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0–0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.

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Acknowledgment

Supported in part by a Grant from the Instituto de Salud Carlos III (C03/02). TPMT determinations were performed by a project of the “Ministerio de Educación y Cultura” (PM 98-0154), different agreements University-Company (60/2002, 7/2002), and a contract of collaboration with the Cytochrome spin-off (64/2003). They have all been financed by UCB-Celltech Pharma. Patient samples were submitted by hundreds of specialists and hospitals throughout Spain. We especially thank physicians, clinical laboratory specialists, and nurses for their commitment to this program.

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Authors and Affiliations

  1. Servicio de Aparato Digestivo Hospital Universitario de la Princesa, Universidad Autónoma, Playa de Mojácar 29, Urb, Bonanza, 28669, Boadilla del Monte, Madrid, Spain

    Javier P. Gisbert, Marta Luna, Yago González-Lama, José María Pajares & José Maté

  2. Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain

    Fernando Gomollón

  3. Departamento Médico, Celltech UCB Pharma, Brussels, Belgium

    Carlos Cara

  4. Unidad de Toxicología Molecular Hepática Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    Luis G. Guijarro

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  1. Javier P. Gisbert
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Correspondence to Javier P. Gisbert.

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Gisbert, J.P., Gomollón, F., Cara, C. et al. Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients. Dig Dis Sci 52, 1262–1269 (2007). https://doi.org/10.1007/s10620-006-9119-z

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