Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration

Purpose: Intrathecal methotrexate achieves high concentrations in cerebrosp inal fluid (CSF), but drug distribution throughout the subarachnoid space a fter an intralumbar dose is limited. The objective of this study was to qua ntify methotrexate distribution in CSF after intraventricular and intraveno us administration and to identify factors that influence CSF distribution. Methods: Nonhuman primates (Macaca mulatta) with permanently implanted cath eters in the lateral and fourth ventricles received methotrexate by bolus i njection (0.5 mg) and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into t he lateral ventricle, as well as intravenous infusions. CSF was sampled fro m the lumbar space, fourth ventricle and the subarachnoid space at the vert ex. Methotrexate in CSF and plasma was measured with the dihydrofolate redu ctase inhibition assay. Results: After bolus intraventricular injection, me thotrexate exposure in lumbar CSF ranged from 11% to 69% of that achieved i n the fourth ventricle. During continuous intraventricular infusions, metho trexate steady-state concentrations (C-ss) in lumbar CSF and CSF from the v ertex 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 ventricu lar methotrexate C-ss was lower than the lumbar C-ss and the C-ss in CSF fr om the vertex. Conclusion: Methotrexate CSF distribution after intraventric ular injection was uneven, and at steady-state CSF methotrexate concentrati ons were lower at sites that were more distant from the injection site.