The Effect of Silibinin on the Pharmacokinetics of Ivabradine and N-Desmethylivabradine in Rats.

The objective of this work was to investigate the effect of orally administered silibinin on the pharmacokinetics of ivabradine and its active metabolite N-desmethylivabradine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 1.0 mg/kg ivabradine alone) and the combination group (1.0 mg/kg ivabradine orally coadministered with 30 mg/kg silibinin). The plasma concentration of ivabradine and N-desmethylivabradine were estimated by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and different pharmacokinetic parameters were calculated using the DAS 2.0 software. The pharmacokinetic parameters of t1/2, Cmax, AUC(0-t) and AUC(0-∞) of ivabradine in the combination group were significantly higher than those in the control group (p < 0.01). However, silibinin has no effect on the pharmacokinetics of N-desmethylivabradine. This study demonstrates that silibinin increase plasma concentration of ivabradine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing ivabradine to patients already taking silibinin.