Milk thistle ([MT] Silybum marianum) has been utilized for centuries as a natural remedy for various diseases affecting the liver and biliary tract. It is typically utilized as a concentrated extract derived from the seeds of the MT plant and standardized to a concentration of 70 to 80% of four flavonoid derivatives (silybin A and B, silichristin, and silidianin), collectively referred to as silymarin. Numerous clinical studies have been performed to date assessing various MT formulations for a variety of hepatic disorders. Despite some limitations and methodological flaws MT treatment appears to offer some potential as a treatment for a number of hepatic ailments. However, more rigorous clinical studies are needed. Additionally, a number of in vitro studies have attributed unique and potentially therapeutic biochemical attributes to the parent (i.e. non-conjugated) silybins. At present, there is a dearth of information available relative to the clinical pharmacokinetics of the active MT constituents as well as the drug interaction potential of MT supplements orally ingested by the lay public and potentially, clinical patients. To date, no study assessing MT for a therapeutic indication has also measured silybin isomer concentrations in plasma in a meaningful way. We propose, in a series of studies utilizing our institution's GCRC, to characterize the clinical pharmacokinetics of the 4 major constituents in normal volunteers dosed with a standardized and characterized silymarin supplement as well as to perform a botanical drug interaction study utilizing accepted probe drug methodology in normal volunteers. Foundational studies such as these are required in order to adequately design further clinical trials.
Specific Aim 1 : To determine the bioavailability and overall pharmacokinetics of the major biologically active MT constituents in a standardized MT supplement after consumption of a single MT supplement dose at three different dosage levels and an ensuing steady-state dosing pharmacokinetic assessment.
Specific Aim 2 : To determine the potential of a standard MT supplement to participate in drug interactions by assessing its ability to induce/inhibit CYP3A4, CYP2D6, CYP2C9 and CYP1A2. Although fundamental to the appropriate design of any clinical trial, these pharmacokinetic characteristics of MT constituents are largely unknown. The proposed exploratory studies will provide a foundational basis for the design of clinical studies allowing the appropriate choice of formulation, dosages and dosing schedules of MT supplements. Further, the important issues of concomitant pharmacotherapy and drug interactions will be addressed.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT002817-03
Application #
7210644
Study Section
Special Emphasis Panel (ZAT1-JH (05))
Program Officer
Hopp, Craig
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$142,569
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Wang, Xinwen; Zhu, Hao-Jie; Munoz, Juliana et al. (2015) An ex vivo approach to botanical-drug interactions: a proof of concept study. J Ethnopharmacol 163:149-56
Kawaguchi-Suzuki, Marina; Frye, Reginald F; Zhu, Hao-Jie et al. (2014) The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos 42:1611-6
Zhu, Hao-Jie; Brinda, Bryan J; Chavin, Kenneth D et al. (2013) An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: a dose escalation study. Drug Metab Dispos 41:1679-85
Markowitz, John S; Zhu, Hao-Jie (2012) Limitations of in vitro assessments of the drug interaction potential of botanical supplements. Planta Med 78:1421-7
Brinda, Bryan J; Zhu, Hao-Jie; Markowitz, John S (2012) A sensitive LC-MS/MS assay for the simultaneous analysis of the major active components of silymarin in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 902:1-9