Metabolic disposition and irreversible binding of phencyclidine in rats

Abstract

The metabolic disposition of [ 14C]phencyclidine ([ 14C]PCP) was examined in rats after intratracheal, ip or iv drug administration. [ 14C]PCP absorption by the lung was related to time biphasically after intratracheal administration. At 1 hr after ip administration of [ 14C]PCP (1.8 mg/kg), the concentration of radioactivity in various tissues decreased (in descending order) in the liver, fat, kidney, lung, testes, spleen, heart, and brain. High levels of radioactivity were also detected in the urine and feces, but not in the blood. The radioactivity accumulated by the liver, lung, and kidney was only partially removed by repeated extraction with 80% methanol, indicating the in vivo formation of PCP reactive metabolite which bound with protein irreversibly. Incubation of [ 14C]PCP with rat liver microsomes corroborated that a PCP reactive metabolite was formed. Although hepatic benzpyrene hydroxylase activity decreased significantly after rats were pretreated with PCP, neither microsomal cytochrome P-450 content nor aniline hydroxylase and p-chloro- N-methyl-aniline demethylase activities in lung, liver, and kidney were altered. After a single iv dose of [ 14C]PCP (0.9 mg/kg), biliary radioactivity peaked at about 30 min. Hydroxylated PCP and corresponding glucuronides represented the bulk of the biliary radioactivity. When radioactive bile from a rat pretreated with [ 14C]PCP was administered to a recipient rat intragastrically, radioactivity was found in the bile, indicating enterohepatic recycling of PCP.