The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers.
The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers.
复制标题
DOI：
10.1007/s40262-015-0332-9
复制
发表时间：
2016-04
影响因子：
4.5
通讯作者：
Giacomini KM
中科院分区：
文献类型：
--
作者：
Morrissey KM;Stocker SL;Chen EC;Castro RA;Brett CM;Giacomini KM
在近端小管中，碱性药物通过H+/有机阳离子反向转运蛋白、多药和毒素外排蛋白1（MATE 1）和2K（MATE 2K）的协同作用从肾细胞转运至小管腔。已证明MATE转运蛋白的双重抑制剂对伴随使用的基础药物的药代动力学具有临床相关影响。然而，选择性肾脏有机阳离子转运抑制对二甲双胍等基础药物的药代动力学和药效学的临床影响尚不清楚。本研究旨在体外鉴定选择性MATE 2K抑制剂，并确定其对健康受试者二甲双胍药代动力学和药效学的临床影响。对71种美国食品和药物管理局（FDA）批准的药物进行了基于细胞的战略筛选，以确定能够在临床相关浓度下抑制的肾有机阳离子转运蛋白的选择性抑制剂。根据该筛选，尼扎替丁被鉴定并预测为MATE 2K介导转运的临床强效和选择性抑制剂。在一项开放标签、随机、两阶段交叉药物相互作用（DDI）研究中，在12名健康志愿者中评价了尼扎替丁对二甲双胍药代动力学和药效学的影响。在健康志愿者中，MATE 2K选择性抑制剂尼扎替丁显著增加了二甲双胍的表观分布容积、半衰期和降血糖活性。然而，尽管达到的未结合最大浓度大于MATE 2K介导转运的体外抑制效力（IC 50），但尼扎替丁并未影响二甲双胍的肾脏清除率或净分泌清除率。本研究表明，尼扎替丁对MATE 2K的选择性抑制影响二甲双胍的表观分布容积、组织水平和外周效应。然而，尼扎替丁并未改变二甲双胍的全身浓度或肾脏清除率，表明特异性MATE 2K抑制可能不足以导致碱性药物的肾脏DDI。
In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H+/organic cation antiporters, multidrug and toxin extrusion 1 (MATE1) and 2K (MATE2K). Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. A strategic cell-based screen of 71 U.S. Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. In healthy volunteers, the MATE2K-selective inhibitor, nizatidine, significantly increased the apparent volume of distribution, half-life and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (IC50) of MATE2K-mediated transport, nizatidine did not affect the renal clearance or net secretory clearance of metformin. This study demonstrates that a selective inhibition of MATE2K by nizatidine, affected the apparent volume of distribution, tissue levels and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the renal clearance of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with basic drugs.