Our objective is to develop new gallstone-dissolving agents which are more effective and safer than the bile acids currently in use, namely, chenodeoxycholic acid and ursodeoxycholic acid. Since the 7-methyl substituted 3,7-dihydroxy and 3,7,12-trihydroxy cholanoic acids are not readily 7-dehydroxylated by the intestinal flora and are known to participate in the enterohepatic circulation, these and related compounds merit further investigation. It is therefore proposed to synthesize and characterize new bile acid analogs with alkyl substituents in the 7- (or 6-) position. The biological stability of the new compounds will be studied in mixed fecal cultures and in pure cultures of fecal bacteria. The metabolism of the bile acid analogs (absorption, biotransformation, conjugation, enterohepatic cycling, fecal and urinary excretion) will be examined in the hamster and prairie dog and compared with the metabolism of the naturally occurring bile acids. The effect of the new compounds on cholesterol/bile acid metabolism and on bile composition will be observed in the isolated, perfused prairie dog liver and in the hamster. The toxicity of the bile acid analogs will be evaluated in the hamster and prairie dog (acute and chronic) and in the rabbit which is known to be highly sensitive to 3,7-dihydroxy bile acids and lithocholic acid. Compounds with appropriate properties will be evaluated further in the prairie dog model of cholesterol cholelithiasis to assess their efficacy in the prevention and dissolution of cholesterol gallstones. The studies will aid not only in the development of new and useful drugs for eventual use in man but will elucidate structure-function relationships in the bile acid series, specifically those relating to modifications of cholesterol/bile acid/biliary lipid metabolism. It is further proposed to evaluate a new hamster model of pigment cholelithiasis recently discovered by the applicant. This model employs a nutritionally adequate, semipurified diet containing 0.3% cholesterol. The effect of dietary modifications on the formation, and composition of the stones will be investigated and correlated with bile composition and cholesterol metabolism.
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