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Pharmacotherapeutic group: Bile acid preparations. ATC code: A05AA02.
Pharmacology: Pharmacodynamics: Small amounts of ursodeoxycholic acid are found in human bile.
After oral administration, it reduces cholesterol saturation of the bile by inhibiting cholesterol absorption in the intestine and decreasing cholesterol secretion into the bile. Presumably as a result of dispersion of the cholesterol and formation of liquid crystals, a gradual dissolution of cholesterol gallstones occurs.
According to current knowledge, the effect of ursodeoxycholic acid in hepatic and cholestatic diseases is thought to be due to a relative exchange of lipophilic, detergent-like, toxic bile acids for the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, to an improvement in the secretory capacity of the hepatocytes, and to immune-regulatory processes.
Pharmacokinetics: Orally administered ursodeoxycholic acid is rapidly absorbed in the jejunum and upper ileum through passive transport and in the terminal ileum through active transport. The rate of absorption is generally 60-80%. After absorption, the bile acid undergoes almost complete hepatic conjugation with the amino acids glycine and taurine and is then excreted with the bile. First-pass clearance through the liver is up to 60%.
Depending on the daily dose and underlying disorder or condition of the liver, the more hydrophilic ursodeoxycholic acid accumulates in the bile. At the same time, a relative decrease in other, more lipophilic, bile acids is observed.
Under the influence of intestinal bacteria, there is partial degradation to 7-keto-lithocholic acid and lithocholic acid. Lithocholic acid is hepatotoxic and causes liver parenchyma damage in a number of animal species. In humans, only very small amounts are absorbed, which are sulphated in the liver and thus detoxified, before being excreted in the bile and ultimately in the faeces.
The biological half-life of ursodeoxycholic acid is 3.5-5.8 days.
Toxicology: Preclinical safety data: a) Acute toxicity: Acute toxicity studies in animals have not revealed any toxic damage.
b) Chronic toxicity: 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.
c) Carcinogenic and mutagenic potential: 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.
d) Toxicity to reproduction: In studies in rats, tail aplasia 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-/postnatal development of the offspring.
