The roles of depot injection sites and proximal lymph nodes in the presystemic absorption of fluphenazine decanoate and fluphenazine: ex vivo experiments in rats.

PURPOSE: The release and presystemic absorption of fluphenazine and its decanoate ester from intramuscular depots were investigated.

METHODS

Rats were sacrificed in groups of three at various times after injection of drug or prodrug in sesame oil. Muscle tissues at the injection sites and various lymph nodes were excised. Blood (plasma) was harvested by cardiac puncture.

RESULTS

Following administration of fluphenazine decanoate, the amount of prodrug at the sites of injection declined exponentially (half-life 3.4 days). Highest concentrations of drug and prodrug were found in iliac and hypogastric lymph nodes nearest to injection sites in which both analytes were detectable 28 days post dose. The half-life for the decline of fluphenazine from lymph nodes (4.6 days) was similar to that from plasma (4.3 days). Following administration of fluphenazine base, only 2.8% of the dose remained at the sites of injection after 2 days. Concentrations of drug in iliac and hypogastric lymph nodes were comparable to those in distal lymph nodes. Fluphenazine concentrations in the lymphatic tissues decreased at about the same rate as plasma concentrations.

CONCLUSIONS

The rate limiting step appeared to be slow partitioning of the decanoate from oily deposits at the injection site and proximal lymph nodes with subsequent hydrolysis of the ester group.