NEW 6-SUBSTITUTED BILE-ACIDS - PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES OF 6-ALPHA-METHYL URSODEOXYCHOLIC ACID AND 6-ALPHA-METHYL-7-EPICHOLIC ACID

New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6 alpha-methyl group were synthesized, and their physico-chemical prop erties were studied and compared with those of their natural analogs. The 6 alpha-methyl group slightly increases the lipophilicity and slig htly lowers the critical micellar concentration with respect to the co rresponding natural analogs. Simulated bile 50% enriched with 6 alpha- methyl ursodeoxycholic acid, with a total bile acid/phospholipid ratio of 10/1, demonstrated a higher cholesterol-holding capacity and a fas ter cholesterol gallstone dissolution rate with respect to ursodeoxych olic acid, while 6 alpha-methyl-7-epicholic acid and 7-epicholic acid were much less efficient in these processes. The 6 alpha-methyl analog s were highly stable toward 7-dehydroxylation when incubated with huma n stool in anaerobic conditions. Their transport, metabolism, and effe ct on biliary lipid secretion were evaluated both in rats and hamsters after acute intravenous and intraduodenal infusion at a dose of 10 mu mol/min per kg. In both species, 6 alpha-methyl ursodeoxycholic acid is efficiently secreted in bile, with a cumulative recovery similar to that of ursodeoxycholic acid. The only metabolites of 6 alpha-methyl ursodeoxycholic acid identified were its glycine and taurine amidated forms. 6 alpha-Methyl-7-epicholic acid was efficiently secreted into b ile when infused intravenously, and to a lesser extent when infused in traduodenally, in both rats and hamsters; it was secreted in bile as a midate and also as free acid. When Get-methyl ursodeoxycholic acid, 6 alpha-methyl-7-epicholic acid, ursodeoxycholic acid, and 7-epicholic a cid were chronically administered to hamsters (for 3 weeks, at a dose of 50 mg/kg per day) their accumulation in gallbladder bile was, respe ctively, 25.1%, 4.0%, 15.2%, and 3.4% of the total bile acids. In conc lusion, of the two analogs, only 6 alpha-methyl ursodeoxycholic acid s hows potential as a cholesterol gallstone-dissolving agent. In this re gard, its most important properties are moderate lipophilicity, good m etabolic stability, and better conservation in the enterohepatic circu lation, with respect to ursodeoxycholic acid.