Assessments of CYP‑inhibition‑based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo.
Assessments of CYP‑inhibition‑based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo.
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DOI：
10.1080/13880209.2023.2173253
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发表时间：
2023-12
影响因子：
3.8
通讯作者：
Dai, Da-Peng
中科院分区：
文献类型：
--
作者：
Zhou, Shan;Zhao, Fang-Ling;Wang, Shuang-Hu;Wang, Yi-Ran;Hong, Yun;Zhou, Quan;Geng, Pei-Wu;Luo, Qing-Feng;Cai, Jian-Ping;Dai, Da-Peng
Poziotinib和vonoprazan是两种主要由CYP3A4代谢的药物。然而，它们之间的药物相互作用是未知的。目的：研究波唑替尼与伏诺哌赞的相互作用机制及药代动力学。体外实验采用大鼠肝微粒体（RLMs），经vonoprazan和梯度浓度的poziotinib孵育后，用UPLC-MS/MS测定vonoprazan及其代谢物的含量。体内实验，波唑替尼治疗组大鼠灌胃给予波唑替尼5 mg/kg，每天1次，连用7 d，对照组只给予0.5% CMC-Na。第8天，灌胃vonoprazan 10 mg/kg后，于不同时间点采集尾静脉血，用于vonoprazan及其代谢物的定量。采用DAS和SPSS软件进行药代动力学和统计学分析。体外实验数据表明，poziotinib对vonoprazan的代谢具有非竞争抑制和非竞争抑制的混合模式（IC50 = 10.6 μM）。抑制常数Ki为0.574 μM，结合常数αKi为2.77 μM。体内实验显示，经波齐替尼预处理后，伏诺哌赞的AUC(0- t) （15.05 vs. 90.95 μg/mL·h）和AUC(0-∞)（15.05 vs. 91.99 μg/mL·h）均显著升高。经波唑替尼预处理后，vonoprazan的MRT（0-∞）从2.29 h增加到5.51 h， CLz/F值从162.67 L/kg·h下降到25.84 L/kg·h。Poziotinib对vonoprazan的代谢有明显的抑制作用，临床合用时需多加注意。
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
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DOI：
10.1007/s13318-018-0521-7
发表时间：
2019-04-01
影响因子：
1.9
作者：
Nishihara, Mitsuhiro;Yamasaki, Hitomi;Jenkins, Helen
通讯作者：
Jenkins, Helen
影响因子：
3.9
作者：
Suzuki Y;Yoshihashi T;Takahashi K;Furuya K;Ohkohchi N;Oda T;Homma M
通讯作者：
Homma M
UPLC-MS/MS同时测定大鼠血浆中安非他酮、美托洛尔、咪达唑仑、非那西丁、奥美拉唑和甲苯磺丁脲及其在大鼠细胞色素P450活性研究中的应用
影响因子：
1.8
作者：
Ma, Jianshe;Wang, Shuanghu;Wang, Xianqin
通讯作者：
Wang, Xianqin
影响因子：
11.5
作者：
Garnock-Jones, Karly P.
通讯作者：
Garnock-Jones, Karly P.
影响因子：
3.4
作者：
Oshima T;Miwa H
通讯作者：
Miwa H