当前位置: X-MOL 学术Drug Des. Dev. Ther. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-11-10 , DOI: 10.2147/dddt.s276704
Feifei Chen 1 , Hui Jiang 1 , Jia Xu 1 , Shuanghu Wang 1 , Deru Meng 1 , Peiwu Geng 1 , Dapeng Dai 2 , Quan Zhou 1 , Yunfang Zhou 1
Affiliation  

Purpose: The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo.
Methods: The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague–Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry.
Results: We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine.
Conclusion: Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.

Keywords: gastroduodenal ulcer, gastroesophageal reflux disease, proton pump inhibitors, vonoprazan fumarate


中文翻译:

沃诺拉赞对文拉法辛药代动力学影响的体外和体内大鼠模型评估

目的:本研究的目的是研究沃诺拉赞对文拉法辛体外和体内药代动力学的影响。
方法:使用大鼠肝微粒体研究了沃诺拉赞对文拉法辛的抑制作用的机制。在体外,通过测定 O-去甲基文拉法辛的产生来评估抑制作用。18 只雄性 Sprague-Dawley 大鼠随机分为三组:对照组、沃诺拉赞(5 mg/kg)组和沃诺拉赞(20 mg/kg)组。对大鼠口服单剂量 20 mg/kg 文拉法辛,不加或加用沃诺拉赞。从不同时间点通过尾静脉采集的血样制备血浆,并通过超高效液相色谱-串联质谱法测定文拉法辛及其代谢物 O-去甲基文拉法辛的浓度。
结果:我们观察到 vonoprazan 可以显着降低 O-去甲基文拉法辛的量 (IC 50 = 5.544 μM)。沃诺拉赞通过混合抑制、结合竞争性和非竞争性抑制机制来抑制文拉法辛的代谢。与对照组(不含沃诺拉赞)相比,5 和 20 mg/kg vonoprazan 组的文拉法辛及其代谢物 O-去甲基文拉法辛的药代动力学参数均显着增加,其中 MR O-去甲基文拉法辛增加。
结论:Vonoprazan 在体外和体内显着改变文拉法辛的药代动力学。应进行进一步调查以检查这些对人类的影响。当同时使用沃诺拉赞时,建议对接受文拉法辛维持治疗的个体进行文拉法辛治疗药物监测。

【关键词】:胃十二指肠溃疡 胃食管反流病 质子泵抑制剂 富马酸沃诺拉赞
更新日期:2020-11-12
down
wechat
bug