STUDIES ON FIVE LONG-ACTING CHOLERETICS

¹ Division of Biological Research, G. D. Searle and Co., Chicago, Illinois

Five synthetic compounds were compared with dehydrocholic acid in anesthetized acute biliary fistula dogs. Measurements were made of bile volume, cholic acid and total solids excretion for ten hours. Each agent was administered by vein to dogs selected for a mean weight of approximately 13.5 kgm. Doses were based on equal fractions (1/77) of the acute mouse intraperitoneal LD₅₀, which gave a dose of 20 mgm./kgm. for dehydrocholic acid.

Nearly all test compounds produced a more prolonged excretion of bile than was obtained with dehydrocholic acid. Four of the five compounds stimulated a greater total volume of bile flow than did dehydrocholic acid over the nine-hour test period.

The excretion of cholic acid and total solids was increased briefly during the first hour after administration. This effect appeared dependent upon the flushing of the biliary dead space and the possible excretion of the test compound. During the second and subsequent hours, total solid and cholic acid excretion fell below the control values. As a consequence, the administration of the test agent had no net effect on excretion of solids as compared with untreated controls. The increase in rate of flow and the profound fall in solid concentration were interpreted as indicating that the majority of the five synthetic agents possess a prolonged hydrocholeretic action.

Intestinal absorption was demonstrated for four compounds administered by direct intraduodenal injection of doses equimolar to 20 mgm./kgm. of dehydrocholic acid. The total bile output and the duration of response were similar to the effects obtained with the same doses given intravenously.

The most active compound was SC-2644,-(2,4-dimethoxy-5-cyclohexyl-benzoyl) propionic acid. It augmented the flow of a diluted bile for more than nine hours following intravenous or intraduodenal injection. By vein, 2.8 mgm./kgm. of SC-2644 caused a bile output nearly three times as great as that produced by the equitoxic dose of 20 mgm./kgm. of dehydrocholic acid; and the equimolar dose of 16 mgm./kgm. produced approximately six times as much bile.