The effect of clopidogrel on pharmacokinetics of ivabradine and its metabolite in rats. (September 2015)

• Record Type: Journal Article
• Authors: Sun, Wei; Wang, Zhe; Chen, Hui; Zhang, Xiao-Dan; Huang, Cheng-Ke; Lian, Qing-Quan; Shang-Guan, Wang-Ning; Zhu, Guang-Hui; Hu, Guo-Xin; Wang, Zeng-Shou
• Is Part Of: Drug development and industrial pharmacy. Volume 41:Number 9(2015:Sep.)
• Page Start: 1512
• Page End: 1517
• Publication Date: 2015-09
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmaceutical industry -- Periodicals; Drug Industry -- Periodicals; Technology, Pharmaceutical -- Periodicals; 615.05
• Languages: English
• ISSNs: 0363-9045

Abstract

<abstract> <title>Abstract</title> <p>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<sub>(0 − </sub><italic><sub>t</sub></italic><sub>)</sub>, AUC<sub>(0 − ∞)</sub>, and <italic>C</italic><sub>max</sub> for IVA in the group of IVA + CLO were significantly higher than those in the group of IVA (<italic>p</italic> < 0.01); the half-time (<italic>t</italic><sub>1/2</sub>) in the IVA + CLO group was extended compared to IVA (<italic>p</italic> < 0.01) and CL/F was dropped obviously (<italic>p</italic> < 0.01). The decreases in AUC<sub>(0 − </sub><italic><sub>t</sub></italic><sub>)</sub>, AUC<sub>(0 − ∞)</sub>, and <italic>C</italic><sub>max</sub> for N-demethyl ivabradine in the group of IVA + CLO was significantly compared to the group of IVA (<italic>p</italic> < 0.01). CL/F was higher than IVA (<italic>p</italic> < 0.01) and the <italic>t</italic><sub>1/2</sub> 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).</p> </abstract>