Ulrikka Nygaard1, Nina Toft, Kjeld Schmiegelow. 1. The Pediatric Clinic II, The University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Ulrikka@dadlnet.dk
Abstract
BACKGROUND: Hepatotoxicity with elevation of aminotransferase levels is common during combined methotrexate and thiopurine therapy. However, the mechanism of hepatotoxicity induced by these drugs remains obscure. We have investigated the relationship of a rise in aminotransferase levels to erythrocyte levels of methotrexate and its polyglutamates, 6-thioguanine nucleotides, the major cytotoxic metabolites of 6-mercaptopurine, and methylated metabolites of 6-mercaptopurine generated by thiopurine methyltransferase in competition with the formation of 6-thioguanine nucleotides. METHOD: Weighted means of alanine aminotransferase levels and metabolites of methotrexate and 6-mercaptopurine were calculated from a total of 929 blood samples from 43 patients with acute lymphoblastic leukemia during maintenance therapy with methotrexate and 6-mercaptopurine. RESULTS: Weighted means of aminotransferase levels were significantly related to the average doses of 6-mercaptopurine (r(s) = 0.60, P <.001), erythrocyte levels of methylated metabolites of 6-mercaptopurine (r(s) = 0.63, P <.001), and thiopurine methyltransferase activity (r(s) = 0.32, P =.03). Weighted means of aminotransferase levels were negatively correlated with erythrocyte levels of 6-thioguanine nucleotides and were not related to the average doses of methotrexate or erythrocyte levels of methotrexate and its polyglutamates. CONCLUSION: It was found that 6-mercaptopurine and its methylated metabolites are correlated with the degree of hepatotoxicity during methotrexate and 6-mercaptopurine maintenance therapy. Further studies are needed to explore whether aminotransferase levels could be used as a surrogate marker for methylated metabolites of 6-mercaptopurine and thus to evaluate 6-mercaptopurine treatment compliance.
BACKGROUND:Hepatotoxicity with elevation of aminotransferase levels is common during combined methotrexate and thiopurine therapy. However, the mechanism of hepatotoxicity induced by these drugs remains obscure. We have investigated the relationship of a rise in aminotransferase levels to erythrocyte levels of methotrexate and its polyglutamates, 6-thioguanine nucleotides, the major cytotoxic metabolites of 6-mercaptopurine, and methylated metabolites of 6-mercaptopurine generated by thiopurine methyltransferase in competition with the formation of 6-thioguanine nucleotides. METHOD: Weighted means of alanine aminotransferase levels and metabolites of methotrexate and 6-mercaptopurine were calculated from a total of 929 blood samples from 43 patients with acute lymphoblastic leukemia during maintenance therapy with methotrexate and 6-mercaptopurine. RESULTS: Weighted means of aminotransferase levels were significantly related to the average doses of 6-mercaptopurine (r(s) = 0.60, P <.001), erythrocyte levels of methylated metabolites of 6-mercaptopurine (r(s) = 0.63, P <.001), and thiopurine methyltransferase activity (r(s) = 0.32, P =.03). Weighted means of aminotransferase levels were negatively correlated with erythrocyte levels of 6-thioguanine nucleotides and were not related to the average doses of methotrexate or erythrocyte levels of methotrexate and its polyglutamates. CONCLUSION: It was found that 6-mercaptopurine and its methylated metabolites are correlated with the degree of hepatotoxicity during methotrexate and 6-mercaptopurine maintenance therapy. Further studies are needed to explore whether aminotransferase levels could be used as a surrogate marker for methylated metabolites of 6-mercaptopurine and thus to evaluate 6-mercaptopurine treatment compliance.
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