The Metabolism of Chlorpromazine by Developing Rabbit Liver

Abstract

The developmental pattern of various metabolic pathways involved in the detoxification of chlorpromazine was investigated in rabbits by employing hepatic microsomal enzyme preparations and the isolated perfused liver technique. The sulfoxidation and hydroxylation at position 7 of the phenothiazine ring and mono- and di-demethylation of the aliphatic side-chain of sulfides, sulfoxides, and the hydroxylated derivatives constituted the principal metabolic pathways in adult animals, as characterized by thin-layer chromatography. The activity of 3-day-old liver was limited to the sulfoxidation, hydroxylation, and mono-demethylation of the parent compound while fetal liver, 4 days before term, could only effect the sulfoxidation reaction. The transformation in fetus and neonate appeared to progress better when the livers were perfused with whole blood under physiological conditions. Phenobarbital pretreatment accelerated the formation of various metabolites by both the adult and neonatal livers but not by the fetal livers. The stimulatory effect was completely abolished by in vivo administration of DL-ethionine. SKF 525-A caused a substantial in vivo and in vitro inhibition of the drug-metabolizing activity, regardless of the phenobarbital pretreatment.