Chronic intrathecal administration of dexamethasone sodium phosphate: pharmacokinetics and neurotoxicity in an animal model.

Objective: Although corticosteroids have been used intraspinally for many years, long-term intrathecal administration has not been examined. We have assessed the stability, bioavailability, and safety of continuously delivering the prodrug dexamethasone sodium phosphate into the lumbar subarachnoid space.

Methods: High-performance liquid chromatography studies were performed to determine whether dexamethasone sodium phosphate is degraded either in vials or in an infusion pump at 37 degrees C during a period of weeks. Rats then received implants with a combined intrathecal delivery and microdialysis sampling catheter to determine whether the prodrug is converted to free dexamethasone. A neurotoxicity study was performed in which rats received implants with an intrathecal catheter and were continuously infused with the corticosteroid during a 2-week period.

Results: Dexamethasone sodium phosphate, diluted in saline, is stable at body temperature in vials and implantable infusion pumps for at least 2 weeks. When delivered into the cerebrospinal fluid as a bolus, virtually all of the prodrug is converted to free dexamethasone within 40 minutes. When administered continuously, most of the corticosteroid is in its active form at steady state. Low doses of corticosteroid (< or =12.5 ng/h) produced no side effects or neuropathology in the rats, but a higher dose (125 ng/h) was associated with inflammation in the lumbar subarachnoid space.

Conclusion: Dexamethasone sodium phosphate is a stable prodrug that is efficiently converted to free dexamethasone when delivered intrathecally. Low continuous intrathecal doses seem safe, but higher doses may lead to increased inflammation.