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The Pharmacokinetics of Silymarin Is Altered in Patients with Hepatitis C Virus and Nonalcoholic Fatty Liver Disease and Correlates with Plasma Caspase-3/7 Activity

Divisions of Pharmacotherapy and Experimental Therapeutics (S.J.S., M.V., A.D.M.K., R.L.H.) and Molecular Pharmaceutics (Z.W., P.C.S.), UNC Eshelman School of Pharmacy; and Division of Gastroenterology and Hepatology (M.W.F.), School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20–36%). Area under the curve (AUC_0–24h) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p 0.03), and HCV cirrhosis cohorts (p 0.03), respectively, compared with healthy volunteers (AUC_0–24h = 2021 ng · h/ml). Caspase-3/7 activity correlated with the AUC_0–24h for the sum of all silymarin conjugates among all subjects (R² = 0.52) and was 5-fold higher in the HCV cirrhosis cohort (p 0.005 versus healthy). No correlation was observed with other measures of disease activity, including plasma alanine aminotransferase, interleukin 6, and 8-isoprostane F₂, a measure of oxidative stress. These findings suggest that the pharmacokinetics of silymarin is altered in patients with liver disease. Patients with cirrhosis had the highest plasma caspase-3/7 activity and also achieved the highest exposures for the major silymarin flavonolignans.

This article has been cited by other articles:

				S. R. Miranda, J. K. Lee, K. L. R. Brouwer, Z. Wen, P. C. Smith, and R. L. Hawke Hepatic Metabolism and Biliary Excretion of Silymarin Flavonolignans in Isolated Perfused Rat Livers: Role of Multidrug Resistance-Associated Protein 2 (Abcc2) Drug Metab. Dispos., November 1, 2008; 36(11): 2219 - 2226. [Abstract] [Full Text] [PDF]