Cerebrospinal fluid (CSF) and plasma methotrexate (MTX) concentrations were measured in 76 children and adults who received intrathecal MTX, 12 mg/m2 body surface area, without developing symptoms of lumbar puncture syndrome or drug-induced neurotoxicity. After an initial rapid redistribution of the injected drug, the mean antifolate value in the lumbar CSF declined in a biphasic manner with half-lives of 4.5 and 14 hours. In the plasma the mean MTX concentration reached a peak of 2 X 10(-7) M between 3 and 12 hours after injection and decreased biexponentially thereafter with half-lives of 5.5 and 24 hours. Pharmacokinetic analysis suggested that the predominant mode of MTX transfer from the central nervous system to the systemic circulation is bulk flow absorption of CSF with entrained drug. The two phases of disappearance from the lumbar CSF appear to result from interaction of the convective transport and diffusion between the CSF and brain extracellular fluid (and perhaps some intracellular sites).