home > drugs a-z list > urso (ursodiol) drug center > urso (ursodiol) drug - clinical pharmacology

Mechanism of Action

Urso (ursodiol) diol, a naturally occurring hydrophilic bile acid, derived from cholesterol, is present as a minor fraction of the total human bile acid pool. Oral administration of urso (ursodiol) diol increases this fraction in a dose related manner, to become the major biliary acid, replacing/displacing toxic concentrations of endogenous hydrophobic bile acids that tend to accumulate in cholestatic liver disease. In addition to the replacement and displacement of toxic bile acids, other mechanisms of action include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apotosis of hepatocytes, immunomodulatory effects, and stimulation of bile secretion by hepatocytes and cholangiocytes.

Pharmacodynamics

Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Urso (ursodiol) diol is 7-dehydroxylated more slowly than chenodiol. For equimolar doses of urso (ursodiol) diol and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during urso (ursodiol) diol administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with urso (ursodiol) diol therapy, a reduced capacity to sulfate may exist in some individuals.

Pharmacokinetics

Urso (ursodiol) diol (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of urso (ursodiol) diol is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, urso (ursodiol) diol undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, urso (ursodiol) diol is conjugated with glycine or taurine, then secreted into bile. These conjugates of urso (ursodiol) diol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free urso (ursodiol) diol that can be reabsorbed and reconjugated in the liver. Nonabsorbed urso (ursodiol) diol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some urso (ursodiol) diol is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. In healthy subjects, at least 70% of urso (ursodiol) diol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated urso (ursodiol) diol to plasma protein in healthy subjects or PBC patients. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. Urso (ursodiol) diol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver disease. During chronic administration of urso (ursodiol) diol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, urso (ursodiol) diol constitutes 30-50% of biliary and plasma bile acids.

Clinical Studies

Efficacy of urso (ursodiol) deoxycholic acid administered at 13 to 15 mg/kg/day in 3 or 4 divided doses to PBC patients

A U.S., multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of urso (ursodiol) deoxycholic acid at a dose of 13 to 15 mg/kg/day, administered in 3 or 4 divided doses in 180 patients with PBC (78% received four times a day dosage). Upon completion of the double-blind portion, all patients entered an open-label active treatment extension phase.

Treatment failure, the main efficacy end point measured during this study, was defined as death, need for liver transplantation, histologic progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment failure was significantly (p < 0.01) reduced in the URSO 250 (urso (ursodiol) diol) mg group (20 of 86 (23%)) as compared to the placebo group (40 of 86 (47%)). Time to treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, was also significantly (p < 0.001) delayed in the URSO 250 (urso (ursodiol) diol) treated group (n=86, 803.8±24.9 d vs. 641.1±24.4 d for the placebo group (n=86) on average) regardless of either histologic stage or baseline bilirubin levels ( > 1.8 or ≤ 1.8 mg/dl).

Using a definition of treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, time to treatment failure was significantly delayed in the URSO 250 (urso (ursodiol) diol) group. In comparison with placebo, treatment with URSO 250 (urso (ursodiol) diol) resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM.

Efficacy of urso (ursodiol) diol administered at 14 mg/kg/day as a once daily dose to PBC patients

A second study conducted in Canada randomized 222 PBC patients to urso (ursodiol) diol, 14 mg/kg/day or placebo, administered as a once daily dose in a double-blind manner during a two-year period. At two years, a statistically significant (p < 0.001) difference between the two treatments (n=106 for the URSO 250 (urso (ursodiol) diol) group and n=106 for the placebo group), in favor of urso (ursodiol) diol, was demonstrated in the following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; median percent decrease in bilirubin (-17.12% for the URSO (ursodiol) 250 group vs. +20.00% for the placebo group), transaminases (-40.54% for the URSO 250 (urso (ursodiol) diol) group vs. +5.71% for the placebo group) and alkaline phosphatase (-47.61% for the URSO 250 (urso (ursodiol) diol) group vs. -5.69% for the placebo group); incidence of treatment failure; and time to treatment failure. The definition of treatment failure included: discontinuing the study for any reason; a total serum bilirubin level greater than or equal to 1.5 mg/dl or increasing to a level equal to or greater than two times the baseline level; and the development of ascites or encephalopathy. Evaluation of patients at 4 years or longer was inadequate due to the high drop out rate (n=10 withdrew from the URSO 250 (urso (ursodiol) diol) group vs. n=15 from the placebo group) and small number of patients. Therefore, death, need for liver transplantation, histological progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.

Efficacy of URSO 250 (urso (ursodiol) diol) administered in twice a day versus four times a day divided dosing schedules to PBC patients

A randomized, two-period crossover study in fifty PBC patients compared efficacy of URSO 250 (urso (ursodiol) diol) in twice a day versus four times a day divided dosing schedules in 50 patients for 6 months in each crossover period. Mean percent changes from baseline in liver test results and Mayo risk score (n=46) and serum enrichment with UDCA (n=34) were not statistically significant with any dosage at any time interval. This study demonstrated that UDCA (13 to 15 mg/kg/day) given twice a day is equally effective to UDCA given four times a day. In addition, URSO 250 (urso (ursodiol) diol) was given as a single versus three times a day dosing schedules in 10 patients. Due to the small number of patients in this arm of the study, it was not possible to conduct statistical comparisons between these regimens.

Last reviewed on RxList: 12/28/2009
This monograph has been modified to include the generic and brand name in many instances.