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Drug Metabolism and Disposition Fast Forward
First published on October 3, 2007; DOI: 10.1124/dmd.107.017566

0090-9556/08/3601-65-72$20.00
DMD 36:65-72, 2008

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Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

Zhiming Wen, Todd E. Dumas, Sarah J. Schrieber, Roy L. Hawke, Michael W. Fried, and Philip C. Smith

School of Pharmacy (Z.W., T.E.D., S.J.S., R.L.H., P.C.S.) and School of Medicine (M.W.F.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and PK/PD Modeling and Simulation, Quintiles Inc., Kansas City, Missouri (T.E.D.)

Silymarin, a mixture of polyphenolic flavonoids extracted from milk thistle (Silybum marianum), is composed mainly of silychristin, silydianin, silybin A, silybin B (SBB), isosilybin A (ISBA), and isosilybin B. In this study, the plasma concentrations of free (unconjugated), conjugated (sulfated and glucuronidated), and total (free and conjugated) silymarin flavonolignans were measured using liquid chromatography-electrospray ionization-mass spectrometry, after a single oral dose of 600 mg of standardized milk thistle extracts to three healthy volunteers. Pharmacokinetic analysis indicated that silymarin flavonolignans were rapidly eliminated with short half-lives (1–3 and 3–8 h for free and conjugated, respectively). The AUC0->{infty} values of the conjugated silymarin flavonolignans were 4- to 30-fold higher than those of their free fractions, with SBB (mean AUC0->{infty} = 51 and 597 µg · h/l for free and conjugated, respectively) and ISBA (mean AUC0->{infty} = 30 and 734 µg · h/l for free and conjugated, respectively) exhibiting higher AUC0->{infty} values in comparison with other flavonolignans. Near the plasma peak times (1–3 h), the free, sulfated, and glucuronidated flavonolignans represented approximately 17, 28, and 55% of the total silymarin, respectively. In addition, the individual silymarin flavonolignans exhibited quite different plasma profiles for both the free and conjugated fractions. These data suggest that, after oral administration, silymarin flavonolignans are quickly metabolized to their conjugates, primarily forming glucuronides, and the conjugates are primary components present in human plasma.

Address correspondence to: Dr. Philip C. Smith, School of Pharmacy, CB 7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: pcs{at}email.unc.edu




This article has been cited by other articles:


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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.
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S. J. Schrieber, Z. Wen, M. Vourvahis, P. C. Smith, M. W. Fried, A. D. M. Kashuba, and R. L. Hawke
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
Drug Metab. Dispos., September 1, 2008; 36(9): 1909 - 1916.
[Abstract] [Full Text] [PDF]


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