Comparative pharmacokinetics of abecarnil in rat following single and multiple intragastric treatment and continuous administration via the diet
Krause, W.; Reissmann, F.; Schunack, W.; Schöbel, C.
Drug Metabolism and Disposition the Biological Fate of Chemicals 19(1): 29-35
1991
ISSN/ISBN: 0090-9556 PMID: 1673418 Document Number: 370011
The anxiolytic .beta.-carboline abecarnil was administered to female rats at doses of 10, 50, and 250 mg/kg/day for 4 weeks either intragastrically once a day or continuously via the feed. On days 1, 3, 7, 14, and 28, plasma level profiles (0-24 hr) and, additionally, on day 28, concentration profiles (0-24 hr) in liver, kidney, and brain were determined in identical groups of animals. Fecal excretion of unchanged abecarnil also was determined as a measure for enteric absorption. After both routes of administration, absorption was practically complete. Drug uptake via the feed resulted in a plateau-like plasma level without explicit maxima or minima. Indications were observed for a positive food intake plasma level correlation with lower plasma levels during the day and higher concentrations at night, for a slight increase of drug plasma levels during the 4-week period, and a dose-proportional increase of mean plasma concentrations. Intragastric treatment was characterized by clearly distinguishable absorption and disposition phases with prominent peaks after the 10 and 50 mg/kg doses, a plateau-like plasma level probably due to prolonged absorption after the 250 mg/kg dose, slight accumulation of drug in the plasma during continuous once-daily treatment, and a dose-proportional increase of the AUC. The drug load of the animals measured as concentrations in plasma and tissues was different after both routes of administration. Peak plasma levels were greater after intragastric treatment by a factor of 5, and the AUC was double compared to the feed experiment. Drug levels in tissues were higher after intragastric treatment not only absolutely but also relative to the respective plasma level. Intragastric treatment and administration via the feed are not equivalent pharmacokinetically and, therefore, might result in different toxic effects.