Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates.
OBJECTIVE
Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak 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 ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmacokinetics of MTX after intralumbar and intraventricular administration.


METHODS
Nonhuman primates (Macaca mulatta) with permanently 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 prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure.


RESULTS
Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX.


CONCLUSIONS
The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.
Salzer
W
W
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA. wanda.salzer@keesler.af.mil
Widemann
B
B
McCully
C
C
Adamson
P C
PC
Balis
F M
FM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002552:Cerebral Ventricles / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004333:Drug Administration Routes; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008161:Lumbosacral Region; D008253:Macaca mulatta; D008727:Methotrexate / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology*; D018675:Toxicity Tests; D014528:Uricosuric Agents / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D014528:Uricosuric Agents; D011339:Probenecid; D008727:Methotrexate