The effect of clopidogrel on pharmacokinetics of ivabradine and its metabolite in rats

The present study aimed to investigate the effect of clopidogrel (CLO) on pharmacokinetics of ivabradine (IVA) and its metabolite in rats and develop a reliable method to determine IVA and its metabolite N-demethyl ivabradine in serum. Healthy male SD rats were randomized to be given 0.8 mg/kg IVA or IVA combined with 8 mg/kg CLO. Blood samples were collected at 0.083, 0.16, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after administration. The serum concentrations of IVA and N-demethyl ivabradine were determined by ultra-performance liquid chromatography–mass spectrometry and pharmacokinetic parameters were calculated using DASver3.0 software. The parameters of AUC(0 − t), AUC(0 − ∞), and Cmax for IVA in the group of IVA + CLO were significantly higher than those in the group of IVA (p < 0.01); the half-time (t1/2) in the IVA + CLO group was extended compared to IVA (p < 0.01) and CL/F was dropped obviously (p < 0.01). The decreases in AUC(0 − t), AUC(0 − ∞), and Cmax for N-demethyl ivabradine in the group of IVA + CLO was significantly compared to the group of IVA (p < 0.01). CL/F was higher than IVA (p < 0.01) and the t1/2 was slightly increased. In this study, we find that CLO restrains the metabolism of IVA into N-demethyl ivabradine, which may be related to its competitive inhibition effect on cytochrome P450 isoform 3A4(CYP3A4).