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Drug Metabolism and Disposition Fast Forward
First published on November 29, 2007; DOI: 10.1124/dmd.107.017004

0090-9556/08/3603-589-596$20.00
DMD 36:589-596, 2008

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Hepatobiliary Excretion of Silibinin in Normal and Liver Cirrhotic Rats

Jhy-Wen Wu, Lie-Chwen Lin, Shih-Chieh Hung, Chi-Hung Lin, Chin-Wen Chi, and Tung-Hu Tsai

Institutes of Traditional Medicine (J.-W.W., T.-H.T.), Clinical Medicine (S.-C.H.), Microbiology and Immunology (C.-H.L.), and Pharmacology (C.-W.C), School of Medicine, National Yang-Ming University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Taipei, Taiwan (L.-C.L.); Centers for Disease Control, Department of Health, Taipei, Taiwan (J.-W.W.); Departments of Medical Research and Education (S.-C.H., C.-W.C.) and Surgery (C.-H.L.), Taipei Veterans General Hospital, Taipei, Taiwan; and Department of Education and Research, Renai Branch, Taipei City Hospital, Taipei, Taiwan (T.-H.T., C.-H.L.)

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

Address correspondence to: Dr. Tung-Hu Tsai, Professor, National Yang-Ming University, School of Medicine, Institute of Traditional Medicine, 155, Section 2, Li-Nong Street, Taipei 112, Taiwan. E-mail: thtsai{at}ym.edu.tw




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