Abstract
New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6 alpha-methyl group were synthesized, and their physico-chemical properties were studied and compared with those of their natural analogs. The 6 alpha-methyl group slightly increases the lipophilicity and slightly lowers the critical micellar concentration with respect to the corresponding 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 faster cholesterol gallstone dissolution rate with respect to ursodeoxycholic acid, while 6 alpha-methyl-7-epicholic acid and 7-epicholic acid were much less efficient in these processes. The 6 alpha-methyl analogs were highly stable toward 7-dehydroxylation when incubated with human stool in anaerobic conditions. Their transport, metabolism, and effect on biliary lipid secretion were evaluated both in rats and hamsters after acute intravenous and intraduodenal infusion at a dose of 10 mumol/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 bile when infused intravenously, and to a lesser extent when infused intraduodenally, in both rats and hamsters; it was secreted in bile as amidate and also as free acid. When 6 alpha-methyl ursodeoxycholic acid, 6 alpha-methyl-7-epicholic acid, ursodeoxycholic acid, and 7-epicholic acid were chronically administered to hamsters (for 3 weeks, at a dose of 50 mg/kg per day) their accumulation in gallbladder bile was, respectively, 25.1%, 4.0%, 15.2%, and 3.4% of the total bile acids. In conclusion, of the two analogs, only 6 alpha-methyl ursodeoxycholic acid shows potential as a cholesterol gallstone-dissolving agent. In this regard, its most important properties are moderate lipophilicity, good metabolic stability, and better conservation in the enterohepatic circulation, with respect to ursodeoxycholic acid.
Highlights
New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6a-methyl group were synthesized, and their physico-chemical properties were studied and compared with those of their natural analogs
While the thermodynamic pK, values were similar and the water solubility values of the acid forms were in the same order of magnitude, 6-MUDCA lipophilicity and detergency were greater than those of the natural analog
This study provides new information about the effect on the physico-chemical and biological properties of 7-epicholic acid and ursodeoxycholic acid (UDCA) by the introduction of a methyl group in the CY position
Summary
New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6a-methyl group were synthesized, and their physico-chemical properties were studied and compared with those of their natural analogs. The 6a-methyl analogs were highly stable toward 7-dehydroxylation when incubated with human stool in anaerobic conditions Their transport, metabolism, and effect on biliary lipid secretion were evaluated both in rats and hamsters after acute intravenous and intraduodenal infusion at a dose of 10 pmol/min per kg. The extensive use of ursodeoxycholic acid (UDCA) as a cholesterol gallstone-dissolving drug [1,2,3,4] and its recent application for treatment of cholestatic liver diseases [5,6,7,8] has created the need for developing new, more potent synthetic analogs One reason for this need is that recent studies have indicated that UDCA is only partially accumulated in bile because of incomplete intestinal absorption [9, 10].
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