N-ethyl-tauroursodeoxycholic acid, a novel deconjugation-resistant bile salt analogue: Effects of acute feeding in the rat

Abstract

The purpose of this study was to investigate the physicochemical/biological properties and the effects of acute administration of N-ethyl-tauroursodeoxycholic acid in bile-fistula rats. In vitro determination of high-performance liquid chromatography mobility, octanol/water partitioning, cholesterol solubilizing capacity, and sensitivity to enzyme deconjugation by bacteria and cholylglycine-hydroxylase were performed. In vivo determination of the following was also performed: (1) maximum secretory rate (SRmax) and choleretic/secretory properties during intravenous (IV) administration; (2) site/extent of absorption, effects on bile flow, lipid secretion, and biotransformations after intraduodenal infusion. N-ethyl-tauroursodeoxycholate has a lipophilicity slightly higher than tauroursodeoxycholate, close to taurocholate, and similar cholesterol solubilizing capacity. Deconjugation of N-ethyl-tauroursodeoxycholate was 3.4 ±2.1% after 72 hours, that of tauroursodeoxycholate was 100% after 24 hours. During IV infusion of 300 nmol/min/ 100 g, biliary secretion of N-ethyl-tauroursodeoxycholic and tauroursodeoxycholic acids averaged 185 ±76 (standard deviation) nmol/min/100 g and 221 ± 77 nmol/min/ 100 g (not significant). Increasing infusion rates caused progressive enhancement of bile flow and bile salt secretion until the SRmax was reached (1,305 ± 240 nmol/min/ 100 g for N-ethyl-tauroursodeoxycholic acid and 3,240 nmol/min/100 g for tauroursodeoxycholate). The two bile salts were similarly choleretic. IV feeding of N-ethyltauroursodeoxycholic promoted a greater lipid secretion than tauroursodeoxycholate. After intraduodenal feeding of 800 μmol, 38.8 ± 14.0% and 43.4 ± 12.4% of the two bile salts were recovered in bile. No unconjugated bile salts nor unusual metabolites were detected. Excluding the distal 30 cm of the ileum, only 2.3 ± 0.7% of N-ethyl-tauroursodeoxycholic and 4.0 ± 2.3% of tauroursodeoxycholic acid was absorbed. N-ethyl-tauroursodeoxycholic is a new, hydrophilic, deconjugation-resistant, synthetic bile salt, which, in acute studies in the rat, behaves as the natural analogue with respect to intestinal and hepatobiliary properties.