Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

Abstract

Methotrexate [an antineoplastic drug] has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leukoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. The intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in 9 of 12 red blood cell and 3 of 5 liver samples. Persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.