Pharmacology: Pharmacodynamics: Ursodeoxycholic acid, the 7-β-hydroxyepimer of chenodeoxycholic acid (chenodiol), is a naturally occurring, hydrophilic bile acid found in small quantities in normal human bile (normally about 5% of total bile acids) and in the bile of certain animals.
The exact mechanism of action(s) of ursodeoxycholic acid in the dissolution of gallstones has not been fully elucidated, but it has been suggested that the drug suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol.
Despite aqueous insolubility of cholesterol, in the presence of dihydroxy bile acids cholesterol can be solubilized in aqueous media through the dispersion of cholesterol as liquid crystals or micelles.
Appear to have small inhibitory effect on synthesis and secretion of endogenous bile acids into bile, does not appear to affect secretion of phospholipids into bile.
Site of therapeutic action include the liver, bile and gut lumen.
In patients with gallstones, combined actions of ursodeoxycholic acid change the bile from cholesterol-precipitating to cholesterol-solubilizing, which results in dissolution of cholesterol stones.
Pharmacokinetics: About 90% of a therapeutic dose of ursodeoxychoiic acid is absorbed in the small bowel after oral administration. After absorption, ursodeoxycholic acid enters the portal vein and undergoes efficient extraction from portal blood by the liver (there is a large "first-pass" effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodeoxycholic acid in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodeoxycholic acid appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug's therapeutic actions are in the liver, bile, and gut lumen. With repeated dosing, bile ursodeoxycholic acid concentrations reach steady state in about 3 weeks.
Beyond conjugation, ursodeoxycholic acid is not altered or catabolized appreciably by the liver or intestinal mucosa. Ursodeoxycholic acid can be both oxidized and reduced at the 7- carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Free ursodeoxycholic acid, 7-keto-lithocholic acid, and lithocholic acid are relatively insoluble in aqueous media and larger proportions of these compounds are lost from the distal gut into the feces. Reabsorbed free ursodeoxycholic acid is reconjugated by the liver. Eighty percent (80%) of lithocholic acid formed in the small bowel is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to insoluble lithocholyl conjugates that are excreted into bile and lost in feces.