Legalon 70 Capsules/Legalon 140 Capsules Mechanism of Action

Pharmacotherapeutic group: Medicinal products for liver therapy. ATC code: A05BA03.
Pharmacology: Pharmacodynamics: The antitoxic efficacy of silymarin has been demonstrated in animal experiments in numerous models of liver damage, e.g. with poisons of the death cap fungus phalloidin and alpha-amantin, with lanthinides, carbon tetrachloride, galactosamine, thiocetamine and the hepatotoxic frog virus FV3.
The therapeutic effect of silymarin is attributable to the fact that it has several sites of mechanisms of action: Because of its radical capturing powers, silymarin possesses antiperoxidative activity. The pathophysiological process of lipid peroxidation which is responsible for the destruction of cell membranes, is interrupted or prevented. Furthermore, in liver cells, which have already sustained damage, silymarin stimulates protein synthesis and normalises phospholipid metabolism. The overall outcome is that the cell membrane is stabilised and loss of dissolved cell constituents (e.g. transaminases) from the liver cell is restricted or prevented.
Silymarin restricts certain hepatotoxic substances (poisons of the death cap fungus) from gaining entry to the cell.
The enhancement of protein synthesis by silymarin is due to its stimulation of RNA polymerase I, an enzyme which is located in the nucleus. This leads to increased formation of ribosomal RNA and structure and function proteins (enzymes) are therefore synthetised in greater amounts. The outcome is an increase in the repair capacity and the regenerative powers of the liver.
Pharmacokinetics: The principal constituent of silymarin is silibinin. Clinical investigations show that after its absorption in the digestive tract, it is excreted mainly in the bile (>80 percent of the amount absorbed).
As metabolites, glucoronides and sulphates have been demonstrated in the bile, silibinin is assumed to be reabsorbed after being deconjugated, and then enters into an enterohepatic circulation, as has been shown in experimental animals. As might be expected from its predominantly biliary elimination (site of action: liver), blood levels are low and renal elimination is small. The absorption half-life is 2.2 h and the elimination half-life 6.3 h.
When LEGALON is given in therapeutic doses (140 mg silymarin 3 times daily), the levels of silibinin found in human bile are the same after repeated doses and after a single dose. The results show that silibinin does not accumulate in the body.
After repeated administration of silymarin in doses of 140 mg 3 times daily biliary elimination reaches a steady state.
Toxicology: Preclinical safety data: Since silymarin is characterized by exceptionally low toxicity, it can be administered safely in the recommended doses for long periods.
Acute toxicity: Given in single doses by mouth to rats and mice, silymarin proved to be practically non toxic, and the LD₅₀ can be stated as >2000 mg/kg.
Chronic toxicity: In long-term trials extending up to 12 months, rats and dogs were given silymarin by mouth in maximum doses of 2500 or 1200 mg/kg respectively. Neither the laboratory results nor the autopsy findings showed any evidence of toxic effects.
Reproduction toxicity: Fertility studies in rats and rabbits, together with studies of prenatal, perinatal and postnatal toxicity, did not reveal any adverse effects at any of the stages of reproduction (maximum dose tested: 2500 mg/kg). In particular, silymarin showed no evidence of any teratogenic potential.
Mutagenicity: In vitro and in vivo investigations with silymarin yielded negative results.
Carcinogenicity: Appropriate in vivo studies in rodents have not yet been carried out.