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

OBJECTIVE: Although corticosteroids have been used intraspinally for many y ears, long-term intrathecal administration has not been examined. We have a ssessed the stability, bioavailability, and safety of continuously deliveri ng the prodrug dexamethasone sodium phosphate into the lumbar subarachnoid space. METHODS: High-performance liquid chromatography studies were performed to d etermine 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 s ampling catheter to determine whether the prodrug is converted to free dexa methasone. A neurotoxicity study was performed in which rats received impla nts with an intrathecal catheter and were continuously infused with the cor ticosteroid during a 2-week period. RESULTS: Dexamethasone sodium phosphate, diluted in saline, is stable at bo dy 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 admi nistered continuously, most of the corticosteroid is in its active form at steady state. Low doses of corticosteroid (less than or equal to 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 spac e. CONCLUSION: Dexamethasone sodium phosphate is a stable prodrug that is effi ciently converted to free dexamethasone when delivered intrathecally. Low c ontinuous intrathecal doses seem safe, but higher doses may lead to increas ed inflammation.