Effect of diet and gavage on the absorption and metabolism of fluperlapine in the rat

• Published in: Drug metabolism and disposition Vol. 16; no. 2; p. 238
• Main Authors: Dain, J G, Jaffe, J M
• Format: Journal Article
• Language: English
• Published: United States 01.03.1988
• Subjects: Animals; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacokinetics; Biotransformation; Chromatography, High Pressure Liquid; Dibenzazepines - metabolism; Dibenzazepines - pharmacokinetics; Diet; Eating; Feces - analysis; Intestinal Absorption; Intubation, Gastrointestinal; Liver - metabolism; Male; Rats; Rats, Inbred Strains
• ISSN: 0090-9556

Fluperlapine, Sandoz compound NB 106-689, 3-fluoro-6-(4-methyl-1-piperazinyl)-11H-dibenz[b,e]azepine, in a 12-week toxicity study exhibited liver toxicity (moderate to severe hyperlipidosis) when administered to rats in the diet at 40 mg/kg/day and at 80 mg/kg/day, but not by gavage at 80 mg/kg/day. In order to elucidate those factors which might explain these differences in toxicological findings, the effect of mode of administration (diet vs. gavage) on the absorption and metabolism was investigated in rats. Although the peak concentration of radioactivity was earlier (2 hr vs. 15 hr) and higher (3.3 micrograms eq/ml vs. 1.6 micrograms eq/ml) by gavage than by diet, the extent of absorption based on AUC values and excretion of radioactivity was the same. Analysis of plasma and liver extracts for metabolites showed that although the metabolic pathways were the same after diet or gavage, the relative composition of drug and metabolites present was a function of the mode of administration. In the liver, the target organ, after multiple oral doses by the diet mode, 96% of the identified products represented hydroxylation; a minor amount of parent drug was present. After gavage, the drug (32%) and desmethylfluperlapine (25%) together accounted for 54% of the mixture, and hydroxylation accounted for 44%. In plasma after multiple oral doses, a similar trend was observed; there was a greater percentage of the hydroxylated metabolites compared to the nonhydroxylated metabolites after diet administration and an almost similar proportion of these products after gavage administration. It is possible that the observed differences in toxicity could be due to a difference in the exposure of the target organ to drug and metabolites.