Abstract

Male rats received 12.3 micronmol of trifluoperazine (CF3-PER) per kg orally or into the tail vein, and the kinetics of the drug and of its metabolites, 7-hydroxytrifluoperazine and desmethyltrifluoperazine, were followed from 0.5 to 8 hr after dosage. Brain, liver, lung, kidney, and plasma were analyzed by a thin-layer chromatographic method. Following iv injection, the levels of CF3-PER were much higher in brain, lung, kidney, and plasma obtained from the aorta than following oral administration, whereas the metabolite concentrations were very similar after administration by the two routes. However, CF3-PER concentrations in liver did not depend upon the route of administration. In conjunction with this fact, the poor availability of CF3-PER in the central compartment and extrahepatic tissues following oral dosage points to a pronounced first-pass effect. When CF3-PER plasma levels were measured in the portal vein of orally treated rats, the amount of drug absorbed unchanged from the intestine could be demonstrated to be 91% of the dose. A high liver extraction (about 80%) was demonstrated in vivo by sampling hepatic venous blood. Pretreatment of rats with SKF 525-A led to an impaired CF3-PER elimination and to an increase in the liver/plasma ratio. This showed that the liver extraction was due to rapid biotransformation. Orally dosed rats exhibited significantly higher levels of CF3-PER and of its demethylation product in brain, lung, and kidney when they had been pretreated for 3 weeks with 12.3 micronmol of CF3-PER per kg daily po. One and 4 hr after iv injection of 12.3 micronmol of 3H-CF3-PER per kg, total radioactivity in brain equalled the sum of the specifically analyzed compounds, whereas in lung and kidney the tritium quantity was up to 2-fold, and in liver and plasma up to 4-fold the sum of CF3-PER and its two main metabolites.