METABOLISM AND DISPOSITION OF TRIFLUOPERAZINE IN RAT .2. KINETICS AFTER ORAL AND INTRAVENOUS ADMINISTRATION IN ACUTELY AND CHRONICALLY TREATED ANIMALS

  • 1 January 1977
    • journal article
    • research article
    • Vol. 5  (2) , 104-115
Abstract
Male rats received 12.3 .mu.mol 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 0.5-8 h after dosage. Brain, liver, lung, kidney and plasma were analyzed by a TLC method. Following i.v. 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 2 routes. CF3-PER concentrations in liver did not depend upon the route of administration. The poor availability of CF3-PER in the central compartment and extrahepatic tissues following oral dosage points to a pronounced 1st-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 [2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride] led to an impaired CF3-PER elimination and to an increase in the liver/plasma ratio. 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 were pretreated for 3 wk with 12.3 .mu.mol of CF3-PER per kg daily orally. One and 4 h after i.v. injection of 12.3 .mu.mol of 3H-CF3-PER/kg, total radioactivity in brain equalled the sum of the specifically analyzed compounds, whereas in lung and kidney the 3H quantity was up to 2-fold, and in liver and plasma up to 4-fold the sum of CF3-PER and its 2 main metabolites. [Changes in drug metabolism or distribution and accumulation of metabolites should be determined in psychiatric patients undergoing long-term phenothiazine therapy to prevent unwanted effects.].