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Ursodeoxycholic Acid

A Review of its Pharmacological Properties and Therapeutic Efficacy

  • Drug Evaluation
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Summary

Synopsis: Ursodeoxycholic acid1 is the 7β-hydroxy epimer of chenodeoxycholic acid and is normally present in only trace amounts in the bile. Oral administration of pharmacological doses markedly decreases biliary cholesterol saturation. Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with ursodeoxycholic acid in controlled studies of 6 months duration. Patients showing partial gallstone dissolution at that time are likely to continue improving possibly to complete gallstone dissolution with continued therapy. The success rate with ursodeoxycholic acid may be increased to about 80% if more stringent patient selection criteria are applied to include only those with non-calcified floating cholesterol stones of less than 10 to 15mm diameter. Those with calcified stones or stones greater than 15mm diameter are unlikely to respond to ursodeoxycholic acid therapy. The optimal dose in published studies was about 8 to 10 mg/kg/day, which is about half to two-thirds the dose of chenodeoxycholic acid (15 mg/kg/day) achieving approximately equivalent results.

Ursodeoxycholic acid appears to be remarkably well tolerated, with diarrhoea occurring in only a very small proportion of patients. While surgery is clearly the preferred treatment in many patients with symptomatic gallstones, in a carefully selected subgroup of such patients gallstone dissolution therapy with ursodeoxycholic acid offers an important and worthwhile alternative.

Pharmacodynamic Studies: Ursodeoxycholic acid is normally only present as a very small proportion (up to 5 mol %) of the total biliary bile acids. Oral administration of pharmacological doses increases this fraction in a dose-related manner, and ursodeoxycholic acid may become the major biliary bile acid (usually to 40 to 50 mol %). The total bile acid pool size, which is decreased in gallstone patients, may be increased with ursodeoxycholic acid administration, along with increased bile acid secretion rates. Faecal bile acid loss is increased with therapy and cholesterol secretion into the bile is reduced, without a reduction in phospholipids. The cholesterol saturation of bile is decreased, allowing gradual solubilisation of cholesterol from gallstones to occur. This effect appears to be dose related, and as great or greater than that achieved with chenodeoxycholic acid. A combination of ursodeoxycholic acid and chenodeoxycholic acid has been observed to reduce the cholesterol saturation of the bile to a greater extent than either drug alone. Ursodeoxycholic acid and its conjugates have considerably lower cholesterol-solubilising and dissolution properties in vitro than chenodeoxycholic acid and its conjugates, using surgically acquired gallstones and in single and mixed bile salt systems. However, ursodeoxycholic acid and its conjugates are able to continue cholesterol solubilisation beyond its equilibrium solubility by the formation of a liquid crystalline mesophase, thereby complicating the issue of predicting gallstone dissolution simply from cholesterol-solubilising capacities.

In patients with gallstones, the activity of the hepatic enzyme 3-hydroxy-3-methylglutamyl CoA reductase is generally increased. In most studies this is decreased by ursodeoxycholic acid both in vitro and in vivo to ‘normal’ activity levels, although recently this has been the subject of some controversy. The activity of another hepatic enzyme, cholesterol 7α-hydroxylase, appears to increase. Despite changes in hepatic cholesterol metabolism, there is no unequivocal change in serum lipid levels.

Ursodeoxycholic acid has been shown to be relatively free of effects on intestinal function or morphology in in vitro and in vivo studies in animal models and in man, compared with the quite profound and often troublesome intestinal secretagogic effects seen with chenodeoxycholic acid. Toxicology studies in animals, and monitoring of serum liver enzyme concentrations in man, suggest that ursodeoxycholic acid is not likely to adversely affect liver function at pharmacological doses.

Pharmacokinetic Studies: While the physicochemical properties of ursodeoxycholic acid suggest that its solubility may be restricted to the ileum, in practice intestinal absorption after an oral dose is high, with a first-pass clearance of about 50 to 60%. Studies show that passive diffusion occurs, whereupon the drug enters the enterohepatic circulation and is subject to an efficient hepatic extraction mechanism. The ‘spillover’ into the systemic blood supply is therefore minimal. Plasma levels are not clinically important, but may be useful in estimating bioavailability and patient compliance; they reach maximum concentrations at about 60 minutes after ingestion, with another peak recorded at 3 hours.

Ursodeoxycholic acid is rapidly conjugated with glycine and taurine in the liver. There is considerable interspecies differences in the extent to which the parent compound is transformed to its various metabolites, some of which only appear after repeated enterohepatic circulation. Microbial biotransformation of the drug and its metabolites occurs when they leave the enterohepatic circulation, and is responsible for high levels of faecal lithocholic and 7-ketolithocholic acids during ursodeoxycholic acid therapy. Intestinal flora also hydrolyse conjugated drug back to the parent compound and interconvert ursodeoxycholic and chenodeoxycholic acids (a reaction favouring the latter). However, again the differences in metabolic profiles seen with different bacteria indicate species-specific enzyme activity. In certain constitutional hyperbilirubinaemias, hepatic clearance of ursodeoxycholic acid appears to be significantly reduced.

Therapeutic Trials: In open and controlled trials of ursodeoxycholic acid, partial and complete dissolution of cholesterol gallstones has been achieved in about 45 to 60% of patients overall (i.e. in studies applying a wide range of dosage regimens and inclusion/exclusion criteria) usually after 6 months of treatment. This compares with a spontaneous dissolution rate of less than 1%. However interstudy and interpatient results have varied widely. Amongst factors known to influence the response to ursodeoxycholic acid are a number of specific gallstone characteristics. In carefully selected subgroups of patients — those whose gallstones are less than 15mm diameter (and preferably less than 10mm), non-calcified and floating — a ‘success’ rate (partial or complete dissolution) of over 80% may occur. In contrast, large or radio-opaque gallstones are relatively resistant to ursodeoxycholic acid. The generally lower success rates achieved in Japan compared with Europe (primarily Italy) might suggest that an undetermined racial factor may predispose patients to varying degrees of success, although such findings may simply reflect the generally lower dosage regimens studied, or the generally higher incidence of calcified gallstones, in Japanese patients. Continued treatment beyond 6 months is not necessarily associated with improved rates of response to therapy, but results indicate that gallstones which have partially responded to treatment continue to do so if treatment is continued beyond a 6-month period. From published studies, the optimum dose for therapeutic response appears to be about 8 to 10 mg/kg/day, at which dose the ‘success’ rate is at least as high as that with the optimum dose of chenodeoxycholic acid (15 mg/kg/day).

Recurrence of gallstones following dissolution with ursodeoxycholic acid has been reported in a few patients, but the expected rate of recurrence has not yet been established in long term follow-up studies. Several studies report recurrence of gallstones in at least 25% of patients treated with chenodeoxycholic acid. There are no reports of long term prophylactic use of ursodeoxycholic acid to prevent gallstone recurrence. However, even if it is shown to be effective in this way, it is unclear whether such therapy could be justified.

Dyspepsia, epigastric pain, right hypochondriacal pain and other symptoms of biliary and gallstone disease respond, often very rapidly, in about 75 to 85% of patients treated with ursodeoxycholic acid. However, in such patients a high placebo effect is seen, with up to 50% of patients treated with placebo reporting symptomatic improvements.

Side Effects: There have been very few reports of adverse reactions to ursodeoxycholic acid. Of particular interest is the very low incidence of diarrhoea (about 2%) compared with an incidence of up to 50% with therapeutic doses of chenodeoxycholic acid. Liver function tests do not show any clear trend towards abnormally increased values, and indeed many studies show a slight decrease in transaminase serum concentrations in most patients.

Dosage and Administration: For dissolution of gallbladder cholesterol gallstones, the current recommended dosage of ursodeoxycholic acid is 450 or 600 mg/day taken in divided doses with meals, while published studies suggest that 8 to 10 mg/kg/day provides an accurate estimate of optimum dosage, with some evidence suggesting that a single night-time dosage may be suitable. Cholecystography or ultrasonography, carried out at 6 months, provides a means of monitoring success or failure of therapy and forms the basis for the physicians’ decision to withdraw therapy or continue the treatment regimen in patients who have shown an initial partial response.

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    A. Ward, R. N. Brogden, R. C. Heel, T. M. Speight & G. S. Avery

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Various sections of the manuscript reviewed by: M.C. Bateson, Bishop Auckland General Hospital, Bishop Auckland, County Durham, England; F. Bazzoli, Clinica Medica IIIe Gastroenterologica, Università di Bologna, Bologna, Italy; I.A.D. Bouchier, Department of Medicine, Ninewells Hospital and Medical School, Dundee, Scotland; M.C. Carey, Gastroenterology Division, Brigham and Womens Hospital, Boston, Massachusetts, USA; R.H. Dowling, Department of Medicine, Guy’s Hospital and Medical School, London, England; A.F. Hofmann, Division of Gastroenterology, School of Medicine, University of California, San Diego, California, USA; J. Iser, Balwyn North, Victoria, Australia; U. Leuschner, Zentrum der Inneren Medizin Klinik, Johann Wolfgang Goethe-Universität, Frankfurt, West Germany; I. Makino, Hirosaki University School of Medicine, Hirosaki, Japan; C.K. McSherry, Beth Israel Medical Center, Department of Surgery, Beth Israel Medical Center, New York, New York, USA; E. Roda, Clinica Medica IIIe Gastroenterologica, Università di Bologna, Bologna, Italy; G. Salen, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA; J.L. Thistle, Department of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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Ward, A., Brogden, R.N., Heel, R.C. et al. Ursodeoxycholic Acid. Drugs 27, 95–131 (1984). https://doi.org/10.2165/00003495-198427020-00001

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  • DOI: https://doi.org/10.2165/00003495-198427020-00001

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