Ursolin Mechanism of Action

Pharmacodynamics: Mechanism of Action: Anticholelithic: Although the exact mechanism of ursodiol's anticholelithic action is not completely understood, it is known that when administered orally ursodiol is concentrated in bile and decreases biliary cholesterol saturation by suppressing hepatic synthesis and secretion of cholesterol, and by inhibiting its intestinal absorption. The reduced cholesterol saturation permits the gradual solubilization of cholesterol from gallstones, resulting in their eventual dissolution.
Ursodiol increases bile flow. In chronic cholestatic liver disease, ursodiol appears to reduce the detergent properties of the bile salts, thus reducing their cytotoxicity. Also, ursodiol may protect liver cells from the damaging activity of toxic bile acids (e.g., lithocholate, deoxycholate, and chenodeoxycholate), which increase in concentration in patients with chronic liver disease.
Pharmacokinetics: Absorption: About 90% of an oral dose is absorbed in small intestine.
Only small amounts of ursodiol appear in the systemic circulation.
Distribution: Following absorption from the GI tract, ursodiol distributes to the portal vein and undergoes hepatic extraction (about 50% in the absence of liver disease; extent of extraction decreases as severity of liver disease increases) from portal blood by the liver (i.e., there is a large first-pass effect). After the drug is conjugated in the liver, it is distributed into the bile.
Ursodiol in the bile is concentrated in the gallbladder and distributed into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions stimulated by physiologic responses to eating.
During chronic administration (13-15 mg/kg daily), ursodiol becomes a major biliary and plasma bile acid, comprising 30-50% of biliary and plasma bile acids. Following discontinuance of the drug, the concentration of ursodiol in the bile falls exponentially.
It is not known whether ursodiol is distributed into milk.
Plasma Protein Binding: Healthy individuals: ≥ 70% (as unconjugated ursodiol).
Healthy individuals or patients with primary biliary cirrhosis: Extent of protein binding of conjugated ursodiol is not known.
Metabolism: Ursodiol is conjugated with glycine or taurine in the liver and distributed into the bile. Ursodiol conjugates are absorbed into the small intestine by passive and active mechanisms. These conjugates may be deconjugated in the ileum by intestinal enzymes (or by bacteria in the small intestine), creating free ursodiol that can be reabsorbed and reconjugated in the liver.
Unabsorbed ursodiol reaches the colon unchanged, where it is primarily 7-dehydroxylated to form lithocholic acid. Some ursodiol may be epimerized to form chenodiol, which also undergoes 7-dehydroxylation to form lithocholic acid.
A small portion of lithocholic acid is reabsorbed and conjugated in the liver with glycine or taurine, and sulfated at the 3 position. Ursodiol also can be oxidized at the 7-carbon, producing 7-keto-lithocholic acid. Absorbed 7-keto-lithocholic acid is stereospecifically reduced in the liver to chenodiol. A small portion of orally administered ursodiol undergoes bacterial degradation with each cycle of enterohepatic circulation.
Elimination: Ursodiol is excreted principally in the feces. Urinary excretion increases with treatment but remains below 1% except in patients with severe cholestatic liver disease.
Half-life: About 4-6 days.