Journal
PHARMACOLOGY
Volume 85, Issue 6, Pages 350-356Publisher
KARGER
DOI: 10.1159/000312690
Keywords
Paclitaxel; Silibinin; Pharmacokinetics; Bioavailability; CYP3A; P-Glycoprotein
Categories
Ask authors/readers for more resources
Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (4 mg/kg) administration in the presence and absence of silibinin (0.5, 2.5 or 10 mg/kg). The effect of silibinin on the P-gp as well as CYP3A4 activity was also evaluated. Silibinin inhibited CYP3A4 enzyme activity with an IC50 of 1.8 mu mol/l. In addition, silibinin significantly inhibited P-gp activity. Compared to the control group, silibinin significantly (p < 0.05 by 2.5 mg/kg, p < 0.01 by 10 mg/kg) increased the area under the plasma concentration-time curve (65.8-101.7% higher) of oral paclitaxel. Silibinin also significantly increased (p < 0.05 by 2.5 mg/kg, 31.0% higher; p < 0.01 by 10 mg/kg, 52.9% higher) the peak plasma concentration of paclitaxel. Consequently, the absolute bioavailability of paclitaxel was increased by silibinin compared to that in the control group, and the relative bioavailability of oral paclitaxel was increased 1.15- to 2.02-fold. The intravenous pharmacokinetics of paclitaxel were not affected by the concurrent use of silibinin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability in the presence of silibinin could mainly be due to the increased intestinal absorption of paclitaxel via P-gp inhibition. Copyright (C) 2010 S. Karger AG, Basel
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available