ProUrsan Mechanism of Action

Pharmacotherapeutic group: Medicinal products for the therapy of gallbladder diseases; bile acids preparations. ATC Code: A05AA02.
Pharmacology: Pharmacodynamics: Ursodeoxycholic acid (UDCA) is an endogenous tertiary bile acid which occurs in human bile in small amounts. It is synthesized in the liver via 7-ketolithocholic acid, which is a product of bacterial oxidation of chenodeoxycholic acid (CDC). UDCA is more hydrophilic and almost non-toxic in comparison with other bile acids.
After oral administration, UDCA inhibits absorption of cholesterol from the intestine, reduces cholesterol synthesis in the liver and reduces secretion of endogenous cholesterol into the bile. The gradual dissolution of cholesterol gallstones is probably caused by dispersing the cholesterol and forming liquid crystals.
In cholestasis and reflux gastritis, the beneficial effect of ursodeoxycholic acid is given by a change of the ratios of lipophilic bile acids and hydrophilic UDCA concentrations, which is due to the supply of exogenous UDCA and the formation of nontoxic mixed micelles. UDCA forms mixed micelles with apolar bile acid CDC. In these micelles, CDC represents the apolar core, and UDCA the envelope. Thus, toxic CDC is trapped inside the micelle, and the toxic and membrane-damaging effect of reflux fluid in the gastric juice is thus suppressed.
Due to UDCA polar nature, molecular pairs are moreover formed, which can be incorporated into the cellular membranes rich in phospholipids. As a result, the cellular membrane is stabilized and it is no longer susceptible to the aggressive effects of cytotoxic micelles.
This effect is mediated also through UDCA cytoprotective and immunological action.
There are three principal mechanisms of UDCA action in primary biliary cirrhosis: Displacement of apolar bile acids (formation of nontoxic mixed micelles); Stabilization of the cellular membrane; Immunological action.
Paediatric population: Cystic fibrosis: From clinical studies up to 10 years and more, experience is available with UDCA treatment in paediatric patients suffering from hepatobiliary disorders associated with cystic fibrosis (CFAHD). There is evidence that treatment with UDCA can decrease bile duct proliferation, halt progression of histological damage and even reverse hepatobiliary changes if given in early stages of CFAHD. Treatment with UDCA should be started as soon as the diagnosis of CFAHD is made in order to optimize treatment effectiveness.
Pharmacokinetics: Absorption: When given orally, ursodeoxycholic acid is rapidly absorbed in jejunum and in the upper part of ileum by passive, and in the terminal ileum by active transport. Peak plasma concentration is reached 30-60 minutes after administration.
Biotransformation and elimination: After absorption, this bile acid is metabolized by almost complete conjugation with the amino acids glycine and taurine in the liver, and subsequently it is excreted from the liver into the bile.
In the intestine, ursodeoxycholic acid is deconjugated and dehydroxylated to lithocholic acid. Through enterohepatic circulation, this acid is transported to the liver and there it is transformed back to chenodeoxycholic acid and UDCA. With respect to the previously-mentioned transformation it seems that during the treatment with UDCA, the amount of lithocholic acid is important. Lithocholic acid is partially absorbed and bound to sulphate anion and further conjugated with glycine and taurine and excreted in the bile. These derivatives are only to a small extent absorbed in the intestine and they are excreted in the faeces, which represents an effective mechanism of elimination of this toxic bile acid.
Toxicology: Preclinical safety data: Acute toxicity: Mean LD₅₀ values are >5 g/kg in rats, >10 g/kg in mice, and >10 g/kg in dogs.
Subacute toxicity: In the first part, the rats received an oral dose ranging from 0.5 g/kg to 4 g/kg for 5 weeks. No gross dose-dependent pathological or histopathological changes have been observed.
In the second part, the rats received parenteral doses of 62.5 mg/kg, 125 mg/kg, 250 mg/kg and 500 mg/kg. Histopathological findings (liver necrosis, cholangitis, cell proliferation, proliferation of connective fibres and small biliary ducts, renal abscess) were observed at doses of 125 mg/kg and higher.
Mutagenicity: Mutagenic potential are tested using the following tests: reverse mutation test, micronucleus test; chromosomal aberration test, mouse lymphoma mutation test.
The results showed no mutagenic effect of ursodeoxycholic acid.
Carcinogenicity: In two two-year studies in mice, tests were carried out with doses of 25, 150 and 1,000 mg/kg/day. No changes in tumour incidence were observed at doses up to 150 mg/kg/day.