Key result
Clopidogrel significantly increases ivabradine AUC and Cmax while decreasing its metabolite via competitive CYP3A4 inhibition.
Why the study?
The effect of clopidogrel on the pharmacokinetics of ivabradine and its metabolite in rats was not previously investigated.
Does clopidogrel alter the pharmacokinetics of ivabradine in healthy male SD rats?
Does clopidogrel alter the pharmacokinetics of ivabradine in healthy male SD rats?
Answers are grounded in this paper and cite their sources.
Clopidogrel significantly increases ivabradine exposure and decreases its metabolite in rats, suggesting a potential drug-drug interaction via CYP3A4 inhibition.
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).
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Sun et al. (2014) studied Healthy. Clopidogrel combined with ivabradine vs. 0.8 mg/kg IVA alone was evaluated on Pharmacokinetic parameters (AUC, Cmax, t1/2, CL/F) of ivabradine and N-demethyl ivabradine (p=< 0.01). Clopidogrel increased the AUC and Cmax of ivabradine and decreased those of its metabolite N-demethyl ivabradine, likely via competitive inhibition of CYP3A4.
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