Reduced Renal Clearance of a Zwitterionic Substrate Cephalexin in Mate1-Deficient Mice
Reduced Renal Clearance of a Zwitterionic Substrate Cephalexin in Mate1-Deficient Mice
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DOI：
10.1124/jpet.110.169433
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发表时间：
2010-08-10
影响因子：
3.5
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Watanabe, Shingo;Tsuda, Masahiro;Inui, Ken-ichi
多药毒素排泄物1(MATE1/溶质载体47a1)不仅介导了有机阳离子的转运，而且还介导了头孢氨苄等两性离子的转运。然而，MATE1在体内对头孢氨苄的管状分泌的作用尚未阐明。在本研究中，我们通过MATE1进行了头孢氨苄的转运实验，并在Mate1基因敲除[Mate1(-/-)]小鼠中进行了头孢氨苄的药代动力学分析。转人MATE1的人胚胎肾293细胞对头孢氨苄的摄取呈饱和动力学(K-m=5.9+/-0.5 mm)，pH曲线呈钟形，最大吸收pH为7.0。我们证实了小鼠MATE1也转运了头孢氨苄。单次静脉注射头孢氨苄(5 mg/kg)后，Mate1(-/-)小鼠的血浆头孢氨苄浓度高于野生型[Mate1(+/+)]小鼠。与Mate1(+/+)小鼠相比，Mate1(-/-)小鼠60min尿中头孢氨苄排泄量显著减少，肾脏血药浓度显著升高。Mate1(-/-)小鼠的头孢氨苄在肾脏中的清除量约为Mate1(+/+)小鼠的60%，并且似乎接近肌酐清除量。相比之下，阴离子头孢唑林在两只小鼠之间的药代动力学没有显著差异，头孢唑林不是MATE1的底物。在这项研究中，我们证明了MATE1在体内负责肾小管上皮细胞分泌两性离子底物头孢氨苄。
Multidrug and toxin extrusion 1 (MATE1/solute carrier 47A1) mediates the transport of not only organic cations but also zwitterions such as cephalexin. However, the contribution of MATE1 to tubular secretion of cephalexin in vivo has not been elucidated. In the present study, we carried out transport experiments of cephalexin via MATE1 and performed pharmacokinetic analyses of cephalexin in Mate1 knockout [Mate1(-/-)] mice. Cephalexin uptake by human MATE1-expressing human embryonic kidney 293 cells exhibited saturable kinetics (K-m = 5.9 +/- 0.5 mM) and a bell-shaped pH profile with a maximum at pH 7.0. We confirmed that mouse MATE1 also transported cephalexin. After a single intravenous administration of cephalexin (5 mg/kg), Mate1(-/-) mice showed higher plasma concentrations of cephalexin than wild-type [Mate1(+/+)] mice. The urinary excretion of cephalexin for 60 min was significantly reduced, and the renal concentration was markedly increased in Mate1(-/-) mice compared with Mate1(+/+) mice. The renal clearance of cephalexin in Mate1(-/-) mice was approximately 60% of that in Mate1(+/+) mice and seemed to be near the creatinine clearance. In contrast, there were no significant differences between both mice in the pharmacokinetics of anionic cefazolin, which is not a substrate for MATE1. In this study, we demonstrated that MATE1 is responsible for renal tubular secretion of a zwitterionic substrate cephalexin in vivo.