Transport, metabolism, and effect of chronic feeding of cholylsarcosine, a conjugated bile acid resistant to deconjugation and dehydroxylation

Abstract

To test the effect in rodents of chronic ingestion of a bile acid resistant to deconjugation, cholylsarcosine was synthesized and its transport, metabolism, and effect on biliary bile acid and biliary lipid composition were determined in rabbits, hamsters, and rats. Cholylsarcosine was shown to be well absorbed from the ileum but underwent little absorption from the jejunum or colon. When cholylsarcosine was administered in the diet at 140 mumol/kg.day, it was well absorbed and underwent little biotransformation during enterohepatic cycling; however, both bacterial deconjugation and dehydroxylation (without deconjugation) occurred to a small extent. With chronic feeding, cholylsarcosine accumulated to compose 24%-29% of circulating bile acids in all 3 rodent species. It was rapidly lost from the enterohepatic circulation, with a daily fractional turnover rate of 75%-150%, depending on the species. Cholylsarcosine caused no change in liver tests or hepatic morphology and did not influence biliary lipid secretion. When cholyltaurine was fed, it was also absorbed, but, in contrast to cholylsarcosine, was rapidly deconjugated and dehydroxylated to form deoxycholic acid. The deoxycholic acid accumulated in the enterohepatic circulation, as evidenced by a slow fractional turnover rate of 26%-40% per day, depending on the species. It is concluded that cholylsarcosine is absorbed from the ileum, has an enterohepatic circulation, does not undergo appreciable deconjugation or dehydroxylation in these rodents, and is nontoxic. In the rodent, the circulating bile acids can be somewhat enriched when a bile acid resistant to deconjugation is ingested; but the effect on the steady state biliary bile acid composition is less than that obtained when cholyltaurine is administered because cholyltaurine is biotransformed to deoxycholic acid, which in turn is absorbed and has its own efficient enterohepatic circulation.