Effects of Silibinin on the Pharmacokinetics of Carvedilol after Oral Administration in Rats

− This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol after oral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/ kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibition concentration (IC50) of 5.2 μM and 85.4 μM, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under the plasma concentration–time curve was significantly increased by 36.3–57.1%, and the peak concentration was significantly increased by 51.1–88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bioavailability of carvedilol was increased by 1.13to 1.57-fold and the absolute bioavailability was significantly increased by 38.6–59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux of carvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin.