title: The effect of clopidogrel on pharmacokinetics of ivabradine and its metabolite in rats.
abstract: 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).
authors.affiliation: a The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , China .
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Zhang
authors.forename: Cheng-Ke
authors.initials: CK
authors.lastname: Huang
authors.forename: Qing-Quan
authors.initials: QQ
authors.lastname: Lian
authors.forename: Wang-Ning
authors.initials: WN
authors.lastname: Shang-Guan
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Zhu
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.forename: Zeng-Shou
authors.initials: ZS
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001552:Benzazepines / Q000493:pharmacokinetics*; D002317:Cardiovascular Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D006207:Half-Life; D000077550:Ivabradine; D008297:Male; D013058:Mass Spectrometry; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077550:Ivabradine; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine
keywords: CYP3A4; Clopidogrel; cytochrome P450; ivabradine; pharmacokinetics