Received for publication July 11, 2007.
Revised September 30, 2007.
Accepted for publication October 1, 2007.

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

Abstract

Silymarin, a mixture of polyphenolic flavonoids extracted from milk thistle (Silybum marianum), is mainly composed of silychristin (SC), silydianin (SD), silybin A (SB_A), silybin B (SB_B), isosilybin A (ISB_A), and isosilybin B (ISB_B). In this study, the plasma concentrations of free (unconjugated), conjugated (sulfated and glucuronidated), and total (free and conjugated) silymarin flavonolignans were measured using a liquid chromatography-electrospray ionization-mass spectrometry, after a single oral dose of 600 mg standardized milk thistle extracts to three healthy volunteers. Pharmacokinetic analysis indicated that silymarin flavonolignans were rapidly eliminated with short half-lives (1 to 3 and 3 to 8 h for the free and conjugated, respectively). The AUC₀ values of the conjugated silymarin flavonolignans were 4- to 30-fold higher than those of their free fractions, with SB_B (mean AUC₀ = 51 and 597 µg·h/l for the free and conjugated, respectively) and ISB_A (mean AUC₀ = 30 and 734 µg·h/l for the free and conjugated, respectively) exhibiting higher AUC₀ values in comparison to other flavonolignans. Near the plasma peak times (1 to 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.

Key words: antioxidants, glucuronidation, hepatitis, pharmacokinetics, sulfotransferases