Pharmacology of Silymarin

F. Fraschini, G. Demartini, D. Esposti,

Disclosures

Clin Drug Invest. 2002;22(1) 

In This Article

2. Pharmacokinetics

Silymarin is not soluble in water and is usually administered in capsules as a standard extract (70 to 80% silymarin).

Absorption after oral administration is rather low, with recovery in the bile in rats ranging from 2 to 3%. Peak plasma concentrations are achieved in 4 to 6 hours, both in animal sand in humans. Silymarin is mainly excreted in the bile and, to a lesser degree, in the urine. Its elimination half-life ranges from 6 to 8 hours.[64,65,66] However, other authors[67] reported plasma levels of 500 mg/L (as silibinin) 90 minutes after oral administration of 200 mg/kg of silymarin or of purified S marianum extract in mice.

Silibinin and other components of silymarin are rapidly conjugated with sulfate and glucuronic acid in the liver. The conjugates pass into the plasma and into the bile, where they are found in amounts corresponding to 80% of the total dose administered. An egligible portion is eliminated in the urine. These findings suggest the existence of enterohepatic circulation: intestinal absorption, conjugation in the liver, excretion in the bile, hydrolysis by the intestinal flora, and reuptake in the intestine.[69]

The presence of this cycle makes the study of the intestinal absorption of the natural products very difficult. However, the use of labelled silibinin in the rat has made it possible to show that intestinal absorption of a dose of 20 mg/kg amounts to about 35%. Peak radioactivity is found in the plasma 30 minutes after ingestion.[3]

In 1975, Bülles et al.[68] showed that silibinin is excreted mainly unmodified in the urine after oral or intravenous administration of silibinin N-methylglucamine (2 to 120 mg/kg and 20 mg/kg as silibinin, respectively) in the rat, whereas in the bile it is excreted as metabolites, independently of the route of administration. Silibinin is excreted in minimal quantities in the urine during the 48 hours following oral (2 to 5%) or intravenous (8%) administration. On the contrary, biliary excretion is fairly high during the same period (about 40 to 45% after oral administration of up to 20 mg/kg, and about 80% after intravenous administration). The ratio between dose and quantity excreted in the bile is linear for doses up to 20 mg/kg. Study of the kinetics of biliary excretion after oral administration of 20 mg/kg showed that peak excretion occurs 1 hour after administration. Similar results have been reported by Mennicke.[69]

Tissue distribution of silibinin was studied in SENCAR mice (6 to 7 weeks old) after oral administration of 50 mg/kg.[70] Peak concentrations of free silibinin were recorded after 0.5 hours in the liver, lungs, stomach and pancreas, with values of 8.8 ± 1.6, 4.3 ± 0.8, 123 ± 21, 5.8 ± 1.1µg/g of tissue, respectively. In the skin and prostate, peak concentrations of silibinin were 1.4 ± 0.5 and 2.5 ± 0.4µg/g, respectively, and were reached 1 hour after administration. With regard to sulfate conjugates and ß-glucuronides of silibinin, excluding the lungs and stomach, in which peak values were reached after 0.5 hours, all the other tissues analysed exhibited peak tissue concentrations after 1 hour. The concentrations of free and conjugated silibinin diminished exponentially after 0.5 or 1 hour, with an elimination half-life of 57 to 127 minutes for the free portion and 45 to 94 minutes for the conjugated portion. Assessment of the effects of silibinin 100 and 200 mg/kg/day orally on phase II enzymes revealed a dose-and time-dependent increase in glutathione-S-transferase and quinone reductase activity that was moderately or markedly significant in the liver, lungs, stomach, skin and small intestine.[70]

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