Intrathecal 5-fluorouracil in the rhesus monkey

Area of Science:

• Neuro-oncology
• Pharmacokinetics
• Drug Delivery

Background:

• Meningeal spread of leukemia and solid tumors presents a significant therapeutic challenge.
• Intrathecal chemotherapy is being explored to overcome the blood-brain barrier.
• 5-Fluorouracil (5FU) has shown systemic toxicity when administered intravenously.

Purpose of the Study:

• To evaluate the pharmacokinetic profile of 5-Fluorouracil (5FU) after intrathecal administration in a rhesus monkey model.
• To assess the feasibility of using intrathecal 5FU for treating central nervous system malignancies.

Main Methods:

• Pharmacokinetic analysis of 5FU in cerebrospinal fluid (CSF) after intraventricular and intralumbar administration in rhesus monkeys.
• Evaluation of drug concentration, half-life, and area under the concentration-time curve (AUC).
• Assessment of local toxicity in the spinal cord following intralumbar administration.

Main Results:

• Following intraventricular administration, 5FU exhibited a half-life of 51 minutes and an AUC greater than 18 mM h-1.
• Intralumbar administration of 1 mg 5FU resulted in an AUC of 1235 microM h-1.
• No toxicity was observed with intraventricular 5FU, but local toxicity occurred in the lumbar spinal cord after intralumbar administration.

Conclusions:

• Intrathecal administration of 5FU did not achieve sustained cytotoxic concentrations in the cerebrospinal fluid.
• Local toxicity in the lumbar spinal cord limits the utility of intralumbar 5FU.
• Current intrathecal administration strategies for 5FU are not feasible for achieving therapeutic CSF drug levels.