Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration

Purpose: Intrathecal methotrexate achieves high concentrations in cerebrospinal fluid (CSF), but drug distribution throughout the subarachnoid space after an intralumbar dose is limited. The objective of this study was to quantify methotrexate distribution in CSF after intraventricular and intravenous administration and to identify factors that influence CSF distribution. Methods: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received methotrexate by bolus injection (0.5 mg) and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into the lateral ventricle, as well as intravenous infusions. CSF was sampled from the lumbar space, fourth ventricle and the subarachnoid space at the vertex. Methotrexate in CSF and plasma was measured with the dihydrofolate reductase inhibition assay. Results: After bolus intraventricular injection, methotrexate exposure in lumbar CSF ranged from 11% to 69% of that achieved in the fourth ventricle. During continuous intraventricular infusions, methotrexate steady-state concentrations (C-ss) in lumbar CSF and CSF from the vertex were only 20% to 25% of the ventricular CSF C-ss. The dose, duration of infusion, and infusate volume did not influence drug distribution to the lumbar CSF, but probenicid increased the lumbar to ventricular C-ss ratio, suggesting the involvement of a probenicid-sensitive transport pump in the efflux of MTX from the CSF. During the intravenous infusions, the ventricular methotrexate C-ss was lower than the lumbar C-ss and the C-ss in CSF from the vertex. Conclusion: Methotrexate CSF distribution after intraventricular injection was uneven, and at steady-state CSF methotrexate concentrations were lower at sites that were more distant from the injection site.