Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis

Ursodeoxycholic acid (UDCA) exerts anticholestatic effects in various cholestatic disorders. Several potential mechanisms and sites of action of UDCA have been unraveled in clinical and experimental studies, which could explain its beneficial effects. The relative contribution of these mechanisms to the anticholestatic action of UDCA depends on the type and stage of the cholestatic injury. In early-stage primary biliary cirrhosis and primary sclerosing cholangitis, protection of injured cholangiocytes against the toxic effects of bile acids might prevail. Stimulation of impaired hepatocellular secretion by mainly post-transcriptional mechanisms, including stimulation of synthesis, targeting and apical membrane insertion of key transporters, seems to be relevant in more advanced cholestasis. In intrahepatic cholestasis of pregnancy, stimulation of impaired hepatocellular secretion could be crucial for rapid relief of pruritus and improvement of serum liver tests, as it is in some forms of drug-induced cholestasis. In cystic fibrosis, stimulation of cholangiocellular calcium-dependent secretion of chloride and bicarbonate ions could have a major impact. Inhibition of bile-acid-induced hepatocyte apoptosis can have a role in all states of cholestasis that are characterized by hepatocellular bile-acid retention. Different mechanisms of action could, therefore, contribute to the beneficial effect of UDCA under various cholestatic conditions.