Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice
Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice
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DOI：
10.1124/dmd.108.025015
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发表时间：
2009-05-01
影响因子：
3.9
通讯作者：
Tsuji, Akira
中科院分区：
文献类型：
--
作者：
Kano, Takashi;Kato, Yukio;Tsuji, Akira
肉毒碱/有机阳离子转运蛋白（OCTN）2（SLC 22 A5）在近端小管顶膜上肉毒碱（一种维生素样化合物）的肾小管重吸收中起着关键作用，但其与治疗药物的关系仍有待澄清。本研究的目的是阐明OCTN 2参与β-内酰胺类抗生素头孢定（CER）的肾脏处置，基于对幼年内脏脂肪变性（jvs）小鼠的实验，该小鼠具有octn 2基因的功能缺陷。在野生型小鼠中，恒定静脉输注期间CER的肾脏清除率远高于肾小球滤过率，但随着输注速率的增加而降低，肾脏与血浆浓度比的变化极小，表明存在可饱和的跨顶膜转运机制。静脉注射后，jvs小鼠的血浆浓度曲线和肾脏与血浆浓度比高于野生型小鼠，而jvs小鼠的肾脏清除率远低于野生型小鼠，并可通过肾小球滤过来解释。在表达小鼠OCTN 2的非洲爪蟾卵母细胞中显示了小鼠OCTN 2对CER的摄取。通过OCTN 2的CER转运表现出饱和，K-m类似于3 mM，这与体内肾清除中表现出饱和的肾CER浓度相似。OCTN 2介导的CER转运被肉毒碱抑制，并且不依赖于培养基中的Na+替代。这些结果表明近端小管顶膜上的OCTN 2在小鼠肾脏分泌CER中发挥重要作用。
Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a beta-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidney-to-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K-m of similar to 3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na+ replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice.