Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: AS Grindeks, Krustpils Iela 53, Riga, 1057, Latvia
Pharmacotherapeutic group: bile therapy, bile acid and derivatives
ATC code: A05AA02
Bile acids are the most important components of bile and play a role in stimulating bile production. Bile acids are also important to keep cholesterol dissolved in bile. In healthy individuals, the ratio between concentrations of cholesterol and bile acids in the bile is such that cholesterol is kept dissolved for most of the day. Thus, no gallstones can form (bile is non-lithogenic). In patients with cholesterol stones in the gallbladder, this ratio is altered and the bile is supersaturated with cholesterol (bile is lithogenic). After some time, this may cause precipitation of cholesterol crystals and the formation of gallstones. This medicinal product can convert lithogenic bile into non-lithogenic bile and also gradually dissolve cholesterol gallstones.
Studies into the effect of this medicinal product on cholestasis in patients with impaired biliary drainage and on clinical symptoms in patients with biliary cirrhosis and cystic fibrosis have shown a rapid decline in cholestatic symptoms in the blood (as measured by increased levels of alkaline phosphatase (AP), gamma-GT and bilirubin) and pruritus, as well as decreased fatigue in most patients.
From clinical reports, long-term experience of more than 10 years is available on this medicinal product treatment in paediatric patients with hepatobiliary disorders as a result of cystic fibrosis (CFAHD). It has been demonstrated that treatment with this medicinal product can decrease bile duct proliferation, halt progression of histological damage and even reverse hepatobiliary changes, when it is given at early stage of CFAHD. Treatment with this medicinal product must be initiated as soon as the diagnosis of CFAHD is made, in order to optimise the effect of treatment.
About 60-80% of orally administered ursodeoxycholic acid is rapidly absorbed in jejunum and in upper ileum by passive diffusion and in terminal ileum by active transport.
Following absorption, ursodeoxycholic acid passes into the liver (there is a considerable “first-pass-effect”), where it is conjugated with glycine or taurine and subsequently excreted into the biliary tract. Only a small proportion of ursodeoxycholic acid is found in the systemic circulation and this is renally excreted. After repeated dosing, the ursodeoxycholic acid concentration in bile reaches steady state after about 3 weeks: however, the total concentration of ursodeoxycholic acid is never any higher than about 60 % of the total bile acid concentration in bile, even at high dosages.
With the exception of conjugation, ursodeoxycholic acid is not metabolised. However, a small amount of orally administered ursodeoxycholic acid undergoes bacterial conversion to 7‑keto‑lithocholic acid or lithocholic acid after each enterohepatic circulation, while bacterial deconjugation in the duodenum also takes place. Since ursodeoxycholic acid, 7‑keto‑lithocholic acid and lithocholic acid are relatively poorly soluble in water, a large amount is excreted via the bile in the faeces. Absorbed ursodeoxycholic acid is reconjugated by the liver; 80 % of the lithocholic acid produced in the duodenum is excreted in the faeces, but the remaining 20 % is sulphated following absorption by the liver to insoluble lithocholyl conjugates, which are then excreted via the bile and faeces. Absorbed 7‑keto‑lithocholic acid is reduced to chenodeoxycholic acid in the liver.
Lithocholic acid can cause cholestatic liver damage when the liver is not able to sulphate lithocholic acid. Although a reduced capacity to sulphate lithocholic acid in the liver has been found in some patients, there is provisionally no clinical evidence to suggest that cholestatic liver damage can be associated with ursodeoxycholic acid therapy.
Upon discontinuation of therapy with ursodeoxycholic acid, the concentration of ursodeoxycholic acid in bile after 1 week rapidly declines to 5‑10% of the steady-state concentration.
The biological half-life of ursodeoxycholic acid is approximately 3.5‑5.8 days.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Acute toxicity studies in animals have not revealed any toxic damage.
Subchronic toxicity studies in monkeys revealed hepatotoxic effects in the groups treated with higher dosages. These effects concerned both functional changes (such as liver enzyme changes) and morphological changes, such as bile duct proliferation, portal inflammation and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of ursodeoxycholic acid which, in monkeys (unlike humans), is not degraded. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.
Long-term studies in mice and rats revealed no evidence of ursodeoxycholic acid having carcinogenic potential. In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative.
In studies with rats, tail malformations occurred at a high dosage of 2000 mg/kg of ursodeoxycholic acid. In rabbits, no teratogenic effects were found, although embryotoxic effects were observed from a dose of 100 mg/kg of body weight. This medicinal product had no effect on fertility in rats and had no influence on peri- and post-natal development of the offspring.
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