In the Far East, ursodeoxycholic acid (UDCA) has been used for many centuries in the form of a dry bear bile extract for the treatment of gallbladder and biliary diseases, acute and chronic hepatitis, cirrhosis and steatosis, and even liver failure . In modern medicine, UDCA has been used as a litholytic agent in place of chenodeoxycholic acid (CDCA) only since 1975, when Makino et al. reported its cholesterol bile desaturating ability .
Over the past 20 years, several studies have extended UDCA's therapeutic role to various cholestatic syndromes, such as primary biliary cirrhosis (PBC) , primary sclerosing cholangitis , intrahepatic cholestasis of pregnancy , total parenteral nutrition (TPN)-associated cholestasis , and paediatric cholestasis . UDCA can also be used in the treatment of other diseases, such as inborn errors in bile acids (BA) synthesis  and biliary reflux gastritis .
Few dose-finding studies exist [10,11], and none has evaluated the efficacy and safety of long-term, high-dose therapy with UDCA in cholesterol gallstone disease or cholestatic liver diseases. The efficacy of standard dosages of UDCA has been assessed both as a cholesterol gallstone-dissolving agent and as the choice treatment for PBC. Furthermore, a meta-analysis of the main randomized controlled trials on the efficacy of UDCA at 8–15 mg/kg/day in PBC showed no benefits on the major endpoints considered . The authors of some of the largest multicentre trials in the field argued against the conclusions of this meta-analysis . Nevertheless, we agree with Neuberger  that the debate should not be dropped merely because the scientific community has so far been unable to identify a universally valid endpoint, or because of the lack of a conclusively large number of treated patients with sufficiently long follow-up. For the moment, we believe that it is reasonable to continue to treat our PBC patients with UDCA. Moreover, we also think that an essential issue requires urgent reconsideration: at what dosage is UDCA treatment most effective?
The pharmacokinetics of UDCA
Unconjugated UDCA is absorbed by passive diffusion throughout the intestinal tract, thus the absorbed amount increases proportionally with the dose taken . Glycoconjugated UDCA (GUDCA) is absorbed by both active and passive transport mechanisms, while tauroconjugated UDCA (TUDCA) is transported actively in the terminal ileum.
UDCA absorption is low. Its bioavailability is only 50% whereas that of other BA is 90% . This is due to the low hydric solubility of its non-ionized molecules, which causes low dissolution speed . Optimal solubilization would be possible only at an endoluminal pH greater than 8.4, a value not obtainable in vivo during either pancreatic or duodenal secretion .
Once taken up by hepatocytes, UDCA is conjugated and excreted in bile (its blood levels are extremely low due to the all-important hepatic first-pass clearance). At the same time, free UDCA is also secreted by hepatocytes in bile, where it is actively reabsorbed by cholangiocytes. This phenomenon, called the cholehepatic shunt, is linked to increased biliary bicarbonate secretion. Administration of UDCA leads to an increased BA pool and enhanced BA conjugation by hepatocytes. Whereas the TUDCA : GUDCA ratio is normally 1 : 3, during UDCA therapy it is 1 : 9. Finally, intestinal bacterial flora may partially convert UDCA to lithocholic acid (LCA) and 7-ketolithocholic acid (7-KLCA) . Once back in the human liver, via the enterohepatic circulation, 7-KLCA is converted into CDCA.
CDCA and its dosage debate
Since the 1970s, CDCA has been used for dissolving gallstones . In fact, CDCA both reduces the Biliary Cholesterol Saturation Index and increases the bile acids’ pool size [21–23].
Danzinger et al.  showed that at doses between 0.75 and 4 g/day, CDCA could either completely dissolve gallstones or reduce their volume. CDCA does this not only by increasing the BA pool but also by enhancing the CDCA molar percentage in bile. At the same time, Danzinger et al. observed some side effects, such as diarrhoea and raised transaminase and alkaline phosphatase (ALP) levels. The authors concluded that further studies of the pharmacodynamics and toxicity of CDCA were necessary.
The first prospective CDCA dose-finding study was carried out in 1977 by Gerolami et al. . They tried to identify the most effective dose and the relationship between administered doses and side effects. Doses at 750, 1500 and 3000 mg/day were evaluated. The best solubilization of gallstones was obtained with doses of 1500 mg/day or more. Nevertheless, since side effects (diarrhoea and raised transaminase levels) increased with the administered dose, the authors concluded that the best dose was around 15–20 mg/kg/day.
The need for the higher dosages of CDCA advocated by Danzinger et al. was later confirmed in 1978 by Bateson et al. . However, in clinical practice, as little as 750 mg/day (about 10 mg/kg/day) became the recommended dose. Thus, despite Bateson's demonstration that CDCA is more effective at dosages over 1 g/day (about 15 mg/kg/day) up to the highest well-tolerated dose, in the biggest existing multicentre trial on gallstone dissolution therapy the dosage used was only 750 mg/day . Now that CDCA has been replaced by UDCA, it is to be hoped that UDCA dosages will not suffer a similar fate.
UDCA in primary biliary cirrhosis: an open case?
The first pilot study on the therapeutic efficacy of UDCA dates from 1987, when Poupon et al. reported a good biochemical response at an administered dose of 10 mg/kg/day . This initial study prompted a series of more extensive investigations, in which improvements in liver biochemistry were well documented .
A recent study by Corpechot et al. suggested that UDCA treatment can bring histological benefits . However, the impact of UDCA at 10 mg/kg/day on transplantation-free and overall survival appears to be rather disappointing. Several investigators were unable to report any appreciable differences in terms of major endpoints between UDCA-treated patients and the placebo group . Combination therapies with immunosuppressors or corticosteroids have also been tried, but none has shown additional benefits without major side effects .
Is there a UDCA dosage deficit?
The limited success of UDCA monotherapy in the treatment of PBC makes one wonder whether the drug has been evaluated at ideal doses. The pioneering study by Poupon et al.  adopted the dosages recommended by Tint et al.  for cholesterol lithiasis treatment. These authors had concluded that due to the mechanism of UDCA–CDCA conversion, and UDCA's inability to inhibit primary BA synthesis, the percentage of UDCA in bile could never exceed 62% even when administered in doses above 10 mg/kg/day. Following this debatable axiom, other investigators have continued to use conservative dosages of UDCA in their clinical trials on PBC therapy [31,32].
There is currently a relative dearth of extensive, well-designed dose-finding studies that go beyond the traditional 10 mg/kg/day.
On the other hand, studies into the pharmacokinetics of BA have continued. In 1992, Walker et al. showed that while absorption of CDCA is almost complete at the dosages generally employed, that of UDCA is incomplete and is inversely proportional to the administered dose . In 1998, van Hoogstraten et al. published an interesting study comparing 10- and 20-mg/kg/day doses . The study indicated that the higher dosage produced greater improvement in biochemical response. Thus, the 10-mg/kg/day dose, which today is used almost universally, seems to be suboptimal in PBC therapy.
In 1999, Sauer et al. showed that in cholestatic pathologies, UDCA absorption is vastly reduced . This has prompted a new wave of studies aimed at defining administered/absorbed dose ratios.
A hiatus in the dose-finding saga
To our knowledge, the most recent UDCA dose-finding study for PBC treatment is by Angulo et al., who compared doses of 5–7, 13–15 and 23–25 mg/kg/day in terms of biochemical response, Mayo risk score, UDCA percentage in bile, and side effects . The authors concluded that (1) a dosage of 13–15 mg/kg/day is recommended as first choice, and (2) UDCA absorption is related to the administered dose rather than the histological pattern. However, this study was probably affected by a bias: when the patients complained of serum BA related side effects, they were advised to take cholestyramine, a chelating agent that is capable of bonding and further compromising UDCA absorption.
The BA therapy saga is destined to proceed until clinical trials have been carried out testing suitable dosages of UDCA on sufficiently large groups of patients with a full-length follow-up and using a statistically watertight study design. Only then will we know the true therapeutic potential of UDCA. It also remains to be seen whether combination therapies are objectively advantageous. Moreover, the efficacy of a new pharmaceutical formulation of UDCA salted with sodium awaits verification. In this formulation, the drug could be more bioavailable thanks to a better duodenal absorption.
Finally, how sure are we that we have really been using the best dosages of UDCA to treat PBC? Do we need new, better designed dose-finding studies to explore the efficacy of more elevated dosages?
We have recently performed a pilot study in which progressively increasing doses of UDCA (from 8 to 30 mg/kg/day) were administered to PBC patients, and biochemical response and biliary BA pattern were evaluated in parallel. Even with a limited number of patients and a relatively short follow-up, we were able to demonstrate major improvements in transaminase, gamma-glutamyl transpeptidase (γGT) and ALP serum levels associated with a proportional enrichment of bile in UDCA at the higher dosages and especially at 25–30 mg/kg/day. We think that the effects of long-term high-dose UDCA therapy for PBC now deserve evaluation in terms of histological improvement and overall and transplantation-free survival in randomized, controlled, double-blind trials with patients stratified by stage.
We thank Robin M.T. Cooke for helping with the manuscript.
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