Journal of Lipid Research, Vol 35, 2268-2279, Copyright © 1994 by Lipid Research, Inc.
New 6-substituted bile acids: physico-chemical and biological properties of 6 alpha-methyl ursodeoxycholic acid and 6 alpha-methyl-7- epicholic acid
A Roda, R Pellicciari, C Cerre, C Polimeni, B Sadeghpour, M Marinozzi, GC Forti and E Sapigni
Dipartimento di Scienze Farmaceutiche, Universita di Bologna, Italy.
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.
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