Pharmacokinetics of pure silybin diastereoisomers and identification of their metabolites in rat plasma

The flavonolignan silybin (isolated from the fruits of the milk thistle, Silybum marianum), is a mixture of two diastereoisomers and has anticancer, chemoprotective, hepatoprotective and dermatoprotective properties. This compound is largely used in various functional foods, nutraceutics and food supplements. The pharmacokinetic profiles of optically pure silybins (silybin A and silybin B) were monitored in rat plasma after the intragastric administration (200 mg⋅kg−1 of body weight) of each diastereoisomer. Free (unconjugated) and total (free + conjugated) silybins were monitored for 6 hours by HPLC-PDA. The metabolic profiles of each silybin diastereoisomer were completely different. Our results clearly demonstrate that silybin B (Cmax = 14.50 µg⋅mL−1, Tmax = 2.6 hours, T1/2 = 2.9 hours; total silybin B) was absorbed faster and in a substantially higher amount than silybin A (Cmax = 1.05 µg⋅mL−1, Tmax = 3.9 hours, T1/2 = 2.2 hours; total silybin A). The oral bioavailability of silybin B was estimated to be 0.3%. The AUC 0→6 h (area under the curve) value of total silybin B was 20-fold higher than that of silybin A. SPE-UPLC-MS/MS (solid phase extraction-ultra performance liquid chromatography) was used to identify glucuronides and sulfates (in several isomeric forms) as dominant metabolites of silybin B in rat plasma. Silybin B-7-O-β-glucuronide was the major plasma metabolite of silybin B.