Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates

Purpose: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, p eak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ve ntricular CSF MTX concentrations after intralumbar administration of MTX, a nd to compare the pharmaco kinetics of MTX after intralumbar and intraventr icular administration. Methods: Nonhuman primates (Macaca mulatta) with per manently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept p rone for 1 h after MTX administration, and ventricular CSF was sampled up t o 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area un der the ventricular CSF MTX concentration-time curve (AUC) was used as a me asure of MTX exposure. Results: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricula r CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intral umbar probenecid. Intravenous administration of probenecid did not result i n an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was obs erved in all animals after intralumbar probenecid administration. Ventricul ar CSF MTX concentrations and AUCs were less variable after intraventricula r administration of MTX. Conclusion: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.