Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Laboratoires Mayoly Spindler, 6 avenue de lEurope, BP 51, CHATOU Cedex, France
ATC Code: A05AA02, Bile Acid Preparations
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 cholesterol concentrations and bile acids in the gallbladder 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 has 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. Ursodeoxycholic acid can convert lithogenic bile into non-lithogenic bile and also gradually dissolve cholesterol gallstones.
Studies into the effect of ursodeoxycholic acid on cholestasis in patients with impaired biliary drainage and on clinical symptoms in patients with biliary cirrhosis 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.
Ursodeoxycholic acid occurs naturally in the body. When given orally it is rapidly and completely absorbed. It is 96-98% bound to plasma proteins and efficiently extracted by the liver and excreted in the bile as glycine and taurine conjugates. In the intestine some of the conjugates are deconjugated and reabsorbed. The conjugates may also be dehydroxylated to lithocholic acid, part of which is absorbed, sulphated by the liver and excreted via the biliary tract.
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
Two-year studies in mice and rats revealed no evidence of carcinogenic potential.
In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative.
d) Toxicity to reproduction
In studies in rats, tail malformations occurred after a dose of 2000 mg of ursodeoxycholic acid 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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