An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: a dose escalation study

Abstract

Milk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans have been only partially investigated in humans. Furthermore, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study evaluated the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses of either one (175 mg), two (350 mg), or three (525 mg) milk thistle capsule(s) on three separate study visits. Additionally, the steady-state pharmacokinetic parameters were determined after the subjects were administered one capsule three times daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3 ± 0.9 versus 0.8 ± 0.9 ng/mg creatinine) but failed to reach statistical significance (P = 0.076).

Fig. 1.

Chemical structures of silybin A, silybin B, isosilybin A, isosilybin B, silychristin, silydianin, and taxifolin.

Fig. 2.

Plasma concentrations of silybin A (A), silybin B (B), isosilybin A (C), isosilybin B (D) versus time profiles after oral administration of single doses of one (175 mg), two (350 mg), and three (525 mg) Legalon capsules in healthy volunteers. Data are the means from 13 subjects with error bars presenting S.D.

Fig. 3.

Urinary concentrations of 8-epi-PGF2α in 13 healthy volunteers pre- and postexposure to 175-mg silymarin extract capsules (Legalon) three times daily for 28 days.