Received for publication June 4, 2007.
Revised November 5, 2007.
Accepted for publication November 27, 2007.

Hepatobiliary excretion of silibinin in normal and liver cirrhotic rats

Abstract

Silibinin is the main biologically active flavonolignan extracted from the seeds and fruits of milk thistle, and has the potential efficacy in treating liver disease. The aim of the present study was to examine the hepatobiliary excretion of silibinin and its effect of dimethylnitrosamine (DMN)-induced liver cirrhosis. The experiments were divided into five groups: silibinin 10, 30 and 50 mg/kg alone, silibinin 30 mg/kg co-administered with cyclosporin A (CsA) and silibinin 50 mg/kg with liver cirrhosis induced by DMN groups. The pharmacokinetic data indicated that silibinin had dose-related pharmacokinetics in the dose ranges of 10-50 mg/kg. All the unconjugated or total (unconjugated + conjugated) silibinin concentrations in the bile were significantly higher than those in plasma at the sampling time points at each dose suggesting an active hepatobiliary excretion. When co-administered with CsA, the area under the concentration versus time curve (AUC) in bile was significantly decreased. This suggested that the active silibinin efflux might be partially inhibited by P-glycoprotein (P-gp). In the DMN-induced liver cirrhotic rats, the AUC of plasma unconjugated silibinin was reduced by 53%, however, the total silibinin was increased by 182%. These results together suggest the phase II conjugative reaction of silibinin was blocked by the treatment of DMN.

Key words: analytical chemistry, biliary excretion, hepatobiliary disposition, hepatobiliary transport, HPLC, p-glycoprotein, pharmacokinetics

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