Multiple Transport Mechanisms Involved in the Intestinal Absorption of Metformin: Impact on the Nonlinear Absorption Kinetics
Multiple Transport Mechanisms Involved in the Intestinal Absorption of Metformin: Impact on the Nonlinear Absorption Kinetics
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DOI：
10.1016/j.xphs.2022.01.008
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发表时间：
2022-04-15
影响因子：
3.8
通讯作者：
Inoue, Katsuhisa
中科院分区：
文献类型：
--
作者：
Shirasaka, Yoshiyuki;Seki, Maria;Inoue, Katsuhisa
本研究的目的是探讨多种转运机制对二甲双胍肠道吸收的贡献，重点关注 OCT3、PMAT、THTR2、SERT 和 OCTN2。我们还评估了这些转运蛋白对二甲双胍非线性吸收的影响。对表达 OCT3、PMAT、THTR2 或 SERT 的 MDCKII 细胞的摄取研究证实，二甲双胍是这些转运蛋白的底物。 Decynium22 强烈抑制所有转运蛋白介导的二甲双胍摄取。 7-环戊基抑制 OCT3 和 THTR2 介导的二甲双胍摄取。 AG835、硫胺素和帕罗西汀分别特异性抑制 PMAT、THTR2 和 SERT 介导的二甲双胍摄取。使用这些抑制剂，OCT3、PMAT、THTR2、SERT、OCTN2 等对二甲双胍穿过 Caco2 细胞的肠道渗透的相对贡献估计分别为 9.77%、9.68%、22.2%、1.52%、0% 和 0.66%。 Caco-2 细胞摄取二甲双胍的浓度依赖性分析揭示了非线性动力学，其 Km(app) 值与 THTR2 的值相似。进一步的原位吸收研究表明，在癸鎓22、7-环戊基和硫胺素存在下，二甲双胍的大鼠肠道渗透性显着降低。本研究表明，尽管多种转运机制有助于二甲双胍的肠道吸收，但 THTR2 是二甲双胍非线性吸收的主要决定因素。 (c) 2022 年美国药剂师协会。由爱思唯尔公司出版。保留所有权利。
The aim of this study was to investigate the contributions of multiple transport mechanisms to the intestinal absorption of metformin, focusing on OCT3, PMAT, THTR2, SERT and OCTN2. We also assessed the impact of these transporters on the nonlinear absorption of metformin. Uptake studies with MDCKII cells expressing OCT3, PMAT, THTR2 or SERT confirmed that metformin is a substrate of these transporters. Decynium22 strongly inhibited metformin uptake mediated by all the transporters. 7-Cyclopentyl inhibited OCT3- and THTR2-mediated uptake of metformin. AG835, thiamine and paroxetine specifically inhibited PMAT-, THTR2- and SERT-mediated uptake of metformin, respectively. Using these inhibitors, the relative contributions of OCT3, PMAT, THTR2, SERT, OCTN2 and others to the intestinal permeation of metformin across Caco2 cells were estimated to be 9.77%, 9.68%, 22.2%, 1.52%, 0% and 0.66%, respectively. Concentration-dependent analysis of metformin uptake by Caco-2 cells revealed nonlinear kinetics with the similar Km(app) value to the value for THTR2. Further in situ absorption study demonstrated that rat intestinal permeability of metformin was significantly decreased in the presence of decynium22, 7-cyclopentyl and thiamine. The present study indicated that THTR2 is the major determinant of the nonlinear absorption of metformin, although multiple transport mechanisms contribute to its intestinal absorption. (c) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.