Chemical formula: C₂₄H₄₀O₄ Molecular mass: 392.572 g/mol PubChem compound: 31401
Bile acids are among the most important components of the bile and play a role in the stimulation of bile secretion. Bile acids are also important to keep the cholesterol in bile in solution. In a healthy person, the ratio between the concentration of cholesterol and bile acids in the bile is such that the cholesterol will remain in solution for most of the day. In this case, no gallstones can form (the bile is non-lithogenic). In patients with cholesterol stones in the bile, this ratio is changed and the bile is supersaturated with cholesterol (bile is lithogenic). This may cause a precipitation of cholesterol crystals and the formation of gallstones after some time.
The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.
Investigations of the effect of ursodeoxycholic acid on the cholestasis in patients with impaired biliary drainage and on the clinical symptoms in patients with primary biliary cholangitis and cystic fibrosis have shown that cholestatic symptoms in the blood (to be measured by the increased value of alkaline phosphatase (AF), gamma-GT and bilirubin) and the itch declined rapidly, while also the fatigue decreased in the majority of patients. Moreover, studies seem to indicate a positive benefit-risk ratio of the ursodeoxycholic acid in children and young adult cystic fibrosis patients with mild to moderate hepatobiliary disorders.
From clinical reports long-term experience of 10 years and more has been gained with UDCA therapy in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can inhibit bile duct proliferation, can halt progression of histological damage and even reverse hepato-biliary changes, if it happens at an early stage of CFAHD. The treatment with UDCA should be started as soon as the CFAHD diagnosis is made, in order to optimize the effectiveness of the treatment.
About 90% of the therapeutic dose of the ursodeoxycholic acid is rapidly absorbed in the small intestine after oral administration.
After the absorption, ursodeoxycholic acid is absorbed in the liver (there is a substantial “first-pass-effect”), where it is conjugated with glycine or taurine and then secreted into the bile ducts. Only a small portion of ursodeoxycholic acid is found in the systemic circulation. This is excreted renally. With the exception of conjugation, ursodeoxycholic acid is not metabolised. However, a small fraction of orally administered ursodeoxycholic acid undergoes bacterial conversion to 7-keto-lithocholic acid resp. lithocholic acid after each enterohepatic circulation, while bacterial deconjugation also takes place in the duodenum. Ursodeoxycholic acid, 7-keto-lithocholic acid and lithocholic acid are relatively poorly soluble in water, so a large part of it is excreted via the bile into the faeces. Resorbed ursodeoxycholic acid is conjugated again by the liver; 80% of the lithocholic acid formed in the duodenum is excreted in the faeces, but the remaining 20% of it are sulphated by the liver to insoluble lithocholylconjugates after absorption, which in turn are excreted via the bile and faeces.
Resorbed 7-keto-lithocholic acid is reduced to chenodeoxycholic acid in the liver.
Lithocholic acid can cause cholestatic liver damage, when the liver is unable to sulphate the lithocholic acid. Although a reduced capacity to sulphate the lithocholic acid in the liver is found in some patients, there is for the time being no clinical evidence that cholestatic liver damage can be associated with the therapy using ursodeoxycholic acid.
After repeated dosage, the ursodeoxycholic acid concentration in the bile reaches a “steady state” after approximately 3 weeks: the total concentration of the ursodeoxycholic acid, however, is never higher than about 60% of the total concentration of the bile acid in the bile: also at high doses.
After therapy with ursodeoxycholic acid is stopped, the concentration of ursodeoxycholic acid in bile decreases quickly after 1 week to 5-10% of the “steady-state” concentration.
The biological half-life of ursodeoxycholic acid is approximately 3.5 to 5.8 days.
Acute toxicity studies in animals have not revealed any toxic damage.
Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci 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 detoxified. 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. The tests with ursodeoxycholic acid revealed no relevant evidence of a mutagenic effect.
In studies in rats, tail malformations occurred after a dose of 2000 mg per kg of body weight.
In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.
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