Absorption of intramuscularly administered [14C]haloperidol decanoate in rats

Abstract

When [14C]haloperidol decanoate, an ester of haloperidol and decanoic acid, was given intramuscularly to rats, levels of total radioactivity and haloperidol decanoate in medial iliac and hypogastric sacral lymph nodes nearest to injection sites were the highest in examined lymph nodes and plasma. These lymph node levels became maximum 16 days after administration and declined gradually with half-life (around 14 days) similar to those of plasma total radioactivity, haloperidol decanoate and haloperidol. However, when the labelled ester was given intravenously, plasma total radioactivity disappeared far more rapidly. Much more radioactivity was found in hind limbs whose femoral muscles had been injected than in other body parts, even at late stages after administration. Haloperidol alone was found in the brain after [14C]haloperidol decanoate was given either intramuscularly or intravenously. It was concluded that haloperidol decanoate injected in rat femoral muscle was rate-limitedly distributed in lymph circulation and that the absorbed ester did not penetrate the brain through the blood-brain barrier but formed haloperidol did.

Hydrolysis of haloperidol decanoatein vitro by cultured cells

“…See the reference for detailed experimental conditions. The half-life of the second phase was 2.0 days (8) and that of the first rapidly decreasing phase (the distribution phase) was calculated to be 1.6 h in this study.…”

“…Clinically, the depot antipsychotic haloperidol decanoate is administered intramuscularly as a solution in sesame oil (1,2). In rats, the ester administered intramuscularly was shown to be absorbed first by the lymphatic circulation (8), and this process (whose half-life has been estimated to be around 13 days) was the rate-limiting step in disposition ana metabolism of this ester after this administration route. Therefore, after intramuscular administration of haloperidol decanoate, the hydrolysis of the ester is not the rate-limiting step but the absorption is.…”

“…Lymphocytes are trapped in lymph nodes. In fact, haloperidol decanoate (but not hydrolysate haloperidol) was highly concentrated in lymph nodes nearest to the administration site (8).…”

“…[Carbonyl-P'Cjhaloperidol decanoate with the specific radioactivity of 31.21lCi/mg, [carbonyl-P'C]-haloperidol of 42.7 IlCi/mg and [carboxyl-v'C]-etofenamate (an ester of [carboxyl-v'C] flufenamic acid and diethyleneglycol, used as a reference compound for ester hydrolysis) of 20.4 IlCilmg were prepared as described previously (4,5). Their radiochemical purities were practically 100% as revealed by thin layer chromatography.…”

“…polystyrene culture flask), rat and human lymphocytes (2.0)( 10 6 cells in a glass tube) and established cells, WI-38 cells, L6 cells and BGM cells (1.0)( 10 6 , 4.9)( 10 6 and 1.9)( 10 6 cells, respectively, in a polystyrene culture dish), were washed twice with PBS( -) and the medium was replaced with 5 ml of MEM containing FBS. (8,9). The solvent used was chloroform/methanol (9/l) or cyclohexane /chloroform/acetic acid (60/75/16).…”