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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Bleyer
W A
WA
University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Nelson
J A
JA
Kamen
B A
BA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D006801:Humans; D007278:Injections, Spinal; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013120:Spinal Cord Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate