Effects of Simvastatin on the Metabolism of Vonoprazan in Rats Both in vitro and in vivo.
Effects of Simvastatin on the Metabolism of Vonoprazan in Rats Both in vitro and in vivo.
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DOI：
10.2147/dddt.s365610
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发表时间：
2022
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研究辛伐他汀与伏诺拉赞之间潜在的药物-药物相互作用，为临床合理用药提供科学依据。建立大鼠肝微粒体孵育体系，用UPLC-MS/MS检测伏诺拉赞M-I的主要代谢物，计算辛伐他汀的IC50值，并分析其对伏诺拉赞的抑制作用机制。12只SD大鼠随机分为2组，分别给予辛伐他汀或生理盐水，连续2周。实验当天，两组均给予一次vonoprazan灌胃，然后在不同时间点采血。采用UPLC-MS/MS法测定大鼠血浆中vonoprazan和M-I的浓度。体外实验表明，辛伐他汀可抑制vonoprazan的代谢，其抑制类型属于非竞争性和竞争性混合抑制模型。大鼠体内实验表明，与对照组相比，辛伐他汀组vonoprazan的血药浓度-时间曲线下面积(AUC)减小，清除度(CLZ/F)增大。但与对照组相比，辛伐他汀组M-I表现出更高的AUC和更低的CLZ/F值。提示多剂量辛伐他汀可降低大鼠体内vonoprazan的血药浓度，加快其代谢率。辛伐他汀在体外可抑制vonoprazan的代谢，而体内多剂量的辛伐他汀则表现出相反的作用。综上所述，我们的数据表明辛伐他汀和vonoprazan之间存在相互作用，当它们在临床上联合应用时可能需要额外的护理。
To study the potential drug–drug interactions between simvastatin and vonoprazan and to provide the scientific basis for rational use of them in clinical practice. An incubation system was established with rat liver microsomes, and the main metabolite of vonoprazan M-I was detected by UPLC-MS/MS. The IC50 value of simvastatin was then calculated and its inhibitory mechanism against vonoprazan was also analyzed. Twelve SD rats were randomly divided into 2 groups, then they were given simvastatin or saline for 2 weeks continuously. On the day of the experiment, both groups were intragastrically administered with vonoprazan once, followed by the collection of blood at different time points. Then the plasma concentration of vonoprazan and M-I in rats were detected by UPLC-MS/MS. In vitro experiments revealed that simvastatin could inhibit the metabolism of vonoprazan, and its inhibition type belonged to the mixed non-competitive and competitive inhibition model. In vivo experiments in rats demonstrated that the area under concentration time curve (AUC) of vonoprazan was decreased but the clearance (CLz/F) of it was increased in the simvastatin administrated group, as compared to those of the control group. However, M-I in simvastatin treated group exhibited the higher AUC and lower CLz/F values compared to those in the control group. These data indicated that multiple doses of simvastatin administration could reduce the plasma concentration of vonoprazan and accelerate its metabolic rate in rats. Simvastatin could inhibit the metabolism of vonoprazan in vitro but multiple doses of simvastatin exhibited the opposite effect In vivo. Altogether, our data indicated that an interaction existed between simvastatin and vonoprazan and additional cares might be taken when they were co-administrated in clinic.