Disposition and metabolism of [14C]-haloperidol in rats.

ABSTRACT

Absorption, distribution, excretion and metabolism of [14C]-haloperidol in rats were studied after administration of 5 mg/kg. After oral and intramuscular administration, plasma levels of [14C]-haloperidol radioactivity reached the maximum at 1 h and decreased biphasically. The biphasic elimination was also observed after intravenous administration. The area under plasma level-time curve (AUC) from 0 to 24 h after intramuscular and oral administration was 110 and 87% of AUC after intravenous route, respectively. After intramuscular administration, levels of radioactivity in all tissues examined were higher than plasma and blood levels at 1 h. The lung, Harderian gland, pancreas, kidney, liver, spleen and adrenal had higher levels than other tissues. Most of tissue levels decreased virtually with similar half lives to plasma level and lowered to less than 1 microgram eq/g at 48 h, when negligible recoveries were found in most tissues. Findings concerning distribution obtained by whole-body autoradiography essentially agreed with those by above radiometry. Levels in the placenta and fetus in the pregnant rat were similar to each other and obviously higher than maternal blood level at 1 h after intramuscular administration but no radioactivity was seen in fetus at 48 h. In the lactating rat, milk levels were several times as high as plasma levels and decreased virtually in parallel with plasma levels after intramuscular administration of [14C]-haloperidol. Within 96 h after intramuscular administration, about 99% of administered radioactivity was excreted in urine (about 46%) and feces (about 53%), respectively. About 54% of radioactivity was excreted in the rat bile within 48 h after intramuscular administration. Administration of the bile obtained and thus containing [14C]-haloperidol radioactivity into the duodenum revealed that partial enterohepatic circulation occurred. After intramuscular administration, plasma contained p-fluorobenzoylpropionic acid and p-fluorophenylaceturic acid with comparable concentrations to unchanged haloperidol. Haloperidol alone could be detected in the brain. The liver, kidney, lung and submaxillary gland were also analyzed for their metabolites. Their metabolite compositions differed from each other. Unchanged haloperidol concentration was much higher in all tissues examined than that in plasma. The major urinary and biliary metabolite was p-fluorophenylaceturic acid and conjugates (glucuronide and sulfate) of haloperidol, respectively.