Studies on the Mechanism of Absorption of Depot Neuroleptics: Fluphenazine Decanoate in Sesame oil

Abstract

Purpose. The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs.

Methods. A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses.

Results. After intravenous FLU-D, the pharmacokinetics of the prodrug (mean ± SD) were as follows: Clearance (CL) 42.9 ± 6.3 L/h; terminal half-life (t_1/2) 3.5 ± 0.8 h; volume of distribution (Vd) 216 ± 61 L. The fractional availability of FLU was 1.0 ± 0.2. After intravenous FLU, the volume of distribution of FLU (51 ± 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t_1/2 of FLU was 9.7 ± 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t_1/2 was only 7.7 ± 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid.

Conclusions. The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.