Abstract
Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC0–8 h) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC0–8 h was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC0–8 h (p < 0.05) and 42% lower Cmax (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.
Footnotes
↵2 M.W.F. represents the SyNCH Trial Group.
This work was supported by Cooperative Agreements from the National Institutes of Health National Center for Complementary and Alternative Medicine [Grants U01-AT003571, U01-AT003560, U01-AT003573, U01-AT003566, U01-AT003574], with cofunding from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institutes of Health National Center for Research Resources [Grant RR00046] (General Clinical Research Centers program). In addition, Rottapharm|Madaus, Italy, provided silymarin and placebo and partly funded the trial.
This was an investigator-initiated trial, and Rottapharm|Madaus had no direct or indirect involvement in the design of the trial, data collection, preparation, or submission of the manuscript for this registered (http://clinicaltrials.gov/ct2/show/NCT00389376) investigator-initiated trial. None of the authors have a personal conflict of interest with the manufacturer of any of the marketed silymarin formulations. No official endorsement by the U.S. Food and Drug Administration is intended or should be inferred.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040212.
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ABBREVIATIONS:
- NASH
- nonalcoholic steatohepatitis
- NAFLD
- nonalcoholic fatty liver disease
- HCV
- hepatitis C virus
- Mrp/MRP
- multidrug resistance protein
- AUC
- area under the plasma concentration-time curve
- UGT
- UDP-glucuronosyltransferase
- OATP
- organic anion-transporting polypeptide.
- Received April 22, 2011.
- Accepted August 9, 2011.
- U.S. Government work not protected by U.S. copyright
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