Accumulation of methotrexate in systemic tissues after intrathecal administration

To determine systemic concentrations of methotrexate (MTX) after intrathecal administration in a patient with active leptomeningeal cancer.

Tissues were obtained at autopsy, as requested by the patient, for MTX analysis after 5 doses of the drug were injected into his cerebrospinal fluid (CSF) 6 to 21 days before death. A radioligand assay was used to measure the concentration of MTX in multiple tissues.

Outside the neuraxis, MTX was found in highest concentration in the liver, kidney, lymph nodes, and spleen. Lung and bone also had substantial concentrations. Skeletal muscle had the lowest concentrations of measurable drug and the drug was not detected in the heart. In retrospect, the patient's second course of systemic chemotherapy resulted in greater systemic toxicities because intrathecal MTX was given in conjunction with this course of treatment. In addition, hypersensitivity to intrathecal morphine may have been caused by concomitant intrathecal MTX therapy.

Physicians administering intrathecal MTX must be aware of the paradoxically greater systemic exposure of the drug after intrathecal administration than after systemic administration, the need to expect greater systemic toxicities of intrathecal MTX, and the possibility that it may induce a hypersensitivity to concomitant intrathecal morphine.