评估 vonoprazan 与 poziotinib 及. 基于 CYP 抑制的药物相互作用。
Assessments of CYP‑inhibition‑based drug-drug interaction between vonoprazan and poziotinib and .
机构信息
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, National Center of Gerontology of National Health Commission, Beijing, China.
Peking University Fifth School of Clinical Medicine, Beijing, China.
出版信息
Pharm Biol. 2023 Dec;61(1):356-361. doi: 10.1080/13880209.2023.2173253.
CONTEXT
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.
OBJECTIVE
To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.
MATERIALS AND METHODS
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 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.
RESULTS
experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant K was 0.574 μM and the binding constant αK was 2.77 μM. experiments revealed that the AUC (15.05 90.95 μg/mL·h) and AUC (15.05 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT 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.
CONCLUSIONS
Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
背景
泊马度胺和沃诺拉赞主要通过 CYP3A4 代谢。然而，两者之间的药物相互作用尚不清楚。
目的
研究泊马度胺对沃诺拉赞的相互作用机制和药代动力学。
材料和方法
采用大鼠肝微粒体（RLM）进行实验，孵育 RLMs 与沃诺拉赞和梯度浓度的泊马度胺后，用 UPLC-MS/MS 测定沃诺拉赞及其代谢物的含量。在实验中，给予泊马度胺处理组的大鼠每天灌胃 5mg/kg 泊马度胺一次，共 7 天，对照组仅给予 0.5% CMC-Na。第 8 天，在灌胃给予 10mg/kg 沃诺拉赞后不同时间点采集尾静脉血，用于定量检测沃诺拉赞及其代谢物。使用 DAS 和 SPSS 软件进行药代动力学和统计分析。
结果
实验数据表明，泊马度胺以非竞争和非竞争混合抑制模式抑制沃诺拉赞的代谢（IC=10.6μM）。抑制常数 K 为 0.574μM，结合常数αK 为 2.77μM。实验结果表明，与泊马度胺预处理相比，沃诺拉赞的 AUC（15.05-90.95μg/mL·h）和 AUC（15.05-91.99μg/mL·h）显著增加。沃诺拉赞的 MRT 从 2.29 小时增加到 5.51 小时，而 CLz/F 值从 162.67 减少到 25.84 L/kg·h。
结论
泊马度胺可显著抑制沃诺拉赞的代谢，临床联合用药时需更加注意。
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