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First published on June 19, 2008; DOI: 10.1124/dmd.107.019604

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Received for publication November 5, 2007.
Revised June 18, 2008.
Accepted for publication June 18, 2008.

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

Sarah J Schrieber 1, Zhiming Wen 1, Manoli Vourvahis 1, Philip C. Smith 1, Michael W. Fried 1, Angela D.M. Kashuba 1, Roy L. Hawke 1*

1 University of North Carolina at Chapel Hill

* Address correspondence to: E-mail: rhawke{at}email.unc.edu

Abstract

Background/Aims: Silymarin, used by 30 - 40% of liver disease patients, is comprised of 6 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. Methods: Healthy volunteers and three patient cohorts were administered a single, 600 mg oral dose of milk thistle extract and fourteen blood samples were obtained over 24 hours. Results: Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 - 38% in liver disease cohorts due to accumulation of silychristin (20 - 36%). AUC0-24h for the sum of total silymarin flavonolignans were 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 to healthy volunteers (AUC0-24h=2021 ng*h/ml). Caspase-3/7 activity correlated with the AUC0-24h for the sum of all silymarin conjugates among all subjects (R2=0.52), and was 5-fold higher in HCV cirrhosis cohort (p≤0.005 vs healthy). No correlation was observed with other measures of disease activity including plasma ALT, IL-6, and 8-isoprostane F2{alpha}, a measure of oxidative stress. Conclusions: 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.


Key words: hepatitis, liver disease, oxidative stress, pharmacokinetics




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