Elevated Systemic Elimination of Cimetidine in Rats with Acute Biliary Obstruction: The Role of Renal Organic Cation Transporter OCT2
Elevated Systemic Elimination of Cimetidine in Rats with Acute Biliary Obstruction: The Role of Renal Organic Cation Transporter OCT2
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DOI：
10.2133/dmpk.dmpk-10-rg-004
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发表时间：
2010-01-01
影响因子：
2.1
通讯作者：
Okuda, Masahiro
中科院分区：
文献类型：
--
作者：
Kurata, Tomohiko;Muraki, Yuichi;Okuda, Masahiro
肾小管上皮细胞分泌阳离子药物主要由两类有机阳离子转运蛋白OCT2/SLC22A2和MATE1/SLC47A1控制，它们分别定位于肾小管上皮细胞的基底膜和刷缘膜。然而，对于这些转运蛋白在急性胆汁淤积症中的表达和功能知之甚少。西咪替丁在胆管结扎(BDL)24小时的大鼠体内清除量显著高于假手术大鼠，但两组之间的分布体积没有显著变化。此外，与假手术组大鼠相比，西咪替丁大鼠肾小管净分泌清除量显著增加，肾小球滤过率无明显变化。此外，尽管西咪替丁的肾组织/尿液清除率在两组之间没有差异，但西咪替丁的肾组织/血浆浓度比在BDL大鼠中升高。基础侧有机阳离子转运体rOCT2蛋白在BDL大鼠肾皮质的表达水平明显高于假手术组，而刷缘膜H+/有机阳离子逆向转运体rMATE1蛋白的表达水平与假手术组无显著差异。这些结果表明，急性胆汁淤积使西咪替丁的肾小管分泌增加，这种增加是由于rOCT2的表达水平增加，而不是rMATE1的表达水平增加。
Renal tubular secretion of cationic drugs is dominated by two classes of organic cation transporters, OCT2/SLC22A2 and MATE1/SLC47A1, localized to the basolateral and brush-border membranes of the renal tubular epithelial cells, respectively. However, little is known about the expression and function of these transporters in acute cholestasis. Systemic clearance of cimetidine was significantly higher in rats with bile duct ligation (BDL) for 24 hours than in sham-operated rats, with no significant changes in the volume of distribution between the groups. In addition, net tubular secretory clearance of cimetidine was significantly higher in the BDL rats compared with the sham rats, with no significant changes in the glomerular filtration rate. Moreover, the renal tissue-to-plasma concentration ratio of cimetidine was elevated in BDL rats, although the renal tissue-to-urine clearance ratio of cimetidine was not different between the two groups. The expression level of basolateral organic cation transporter rOCT2 protein in the kidney cortex was markedly higher in BDL rats than that in the sham rats, but that of H+/organic cation antiporter rMATE1 protein in the brush-border membranes was not significantly different between the two groups. These results demonstrate that the renal tubular secretion of cimetidine was increased by acute cholestasis, and this increase was attributable to elevated expression levels of rOCT2 but not of rMATE1 in the rat.