Targeted Disruption of the Multidrug and Toxin Extrusion 1 (Mate1) Gene in Mice Reduces Renal Secretion of Metformin
Targeted Disruption of the Multidrug and Toxin Extrusion 1 (Mate1) Gene in Mice Reduces Renal Secretion of Metformin
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DOI：
10.1124/mol.109.056242
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发表时间：
2009-06-01
影响因子：
3.6
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Tsuda, Masahiro;Terada, Tomohiro;Inui, Ken-ichi
多药和毒素挤出1 （MATE1/SLC47A1）对肾脏和肝脏中有机阳离子的排泄很重要，它位于管腔一侧。虽然其功能和调控特性已被阐明，但其在体内的药代动力学作用尚未阐明。在本研究中，为了阐明MATE1在体内的相关性，我们对小鼠MATE1基因进行了靶向破坏。通过逆转录聚合酶链反应和Western blot分析证实肾脏和肝脏中缺乏Mate1的表达。在野生型[Mate1(+/+)]和敲除Mate1 [Mate1(-/-)]小鼠之间，Octs等其他有机阳离子转运体的mRNA水平没有显著差异。值得注意的是，Mate1（-/-）小鼠是可育的。采用MATE1的典型底物二甲双胍进行药代动力学表征。单次静脉给药二甲双胍（5 mg/kg）后，Mate1（-/-）小鼠血药浓度-时间曲线下面积（AUC(0-60)）增加2倍。与Mate1（+/+）小鼠相比，Mate1（-/-）小鼠静脉给药后60分钟尿中二甲双胍的排泄量显著减少。二甲双胍在Mate1（-/-）小鼠中的肾清除率（CLren）和肾分泌清除率（CLsec）分别约为Mate1（+/+）小鼠的18%和14%。这是第一个证明MATE1在全身清除二甲双胍中起重要作用的报告。
Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is important for excretion of organic cations in the kidney and liver, where it is located on the luminal side. Although its functional and regulatory characteristics have been clarified, its pharmacokinetic roles in vivo have yet to be elucidated. In the present study, to clarify the relevance of MATE1 in vivo, targeted disruption of the murine Mate1 gene was carried out. The lack of Mate1 expression in the kidney and liver was confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. The mRNA levels of other organic cation transporters such as Octs did not differ significantly between wildtype [Mate1(+/+)] and Mate1 knockout [Mate1(-/-)] mice. It is noteworthy that the Mate1(-/-) mice were viable and fertile. Pharmacokinetic characterization was carried out using metformin, a typical substrate of MATE1. After a single intravenous administration of metformin (5 mg/kg), a 2-fold increase in the area under the blood concentration-time curve for 60 min (AUC(0-60)) of metformin in Mate1(-/-) mice was observed. Urinary excretion of metformin for 60 min after the intravenous administration was significantly decreased in Mate1(-/-) mice compared with Mate1(+/+) mice. The renal clearance (CLren) and renal secretory clearance (CLsec) of metformin in Mate1(-/-) mice were approximately 18 and 14% of those in Mate1(+/+) mice, respectively. This is the first report to demonstrate an essential role of MATE1 in systemic clearance of metformin.