Department of Pharmacy, Kyoto University Hospital Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Pharm Res. 2011 May;28(5):1023-30. doi: 10.1007/s11095-010-0348-7. Epub 2010 Dec 15.
In the renal proximal tubular cells, various transporters play important roles in the secretion and reabsorption of drugs. When metabolic acidosis is induced, a number of adaptive changes occur in the kidney. The purpose of this study was to clarify the changes of drug transporters under the acidosis and the effects of these changes on urinary drug excretion.
Wistar/ST rats were given 1.5% NH₄Cl in tap water for 48 h to induce the acidosis. Pharmacokinetics of PSP or metformin was evaluated. In addition, expression levels of drug transporters were examined by Western Blotting.
The renal clearance of PSP was markedly decreased, whereas the creatinine clearance and renal clearance of metformin were unchanged. Furthermore, Western blots indicated that the protein expression level of organic anion transporter (OAT) 3 was decreased. In contrast to OAT3 levels, OAT1 and organic cation transporter (OCT) 2 levels were unaffected. An immunohistochemical analysis showed that the OAT3 protein in the proximal tubules was localized in the basolateral membrane both of the normal and the acidosis rats.
The decrease of renal excretion of anionic drugs during metabolic acidosis might be partly due to a reduction in the level of OAT3 protein.
在肾近端肾小管细胞中，各种转运体在药物的分泌和重吸收中发挥重要作用。当发生代谢性酸中毒时，肾脏会发生许多适应性变化。本研究旨在阐明酸中毒下药物转运体的变化及其对尿液中药物排泄的影响。
用自来水给予 Wistar/ST 大鼠 1.5%氯化铵 48 小时以诱导酸中毒。评估 PSP 或二甲双胍的药代动力学。此外，通过 Western Blotting 检查药物转运体的表达水平。
PSP 的肾清除率明显降低，而肌酐清除率和二甲双胍的肾清除率不变。此外，Western blot 表明有机阴离子转运体（OAT）3 的蛋白表达水平降低。与 OAT3 水平相反，OAT1 和有机阳离子转运体（OCT）2 水平不受影响。免疫组织化学分析表明，正常和酸中毒大鼠的近端肾小管中的 OAT3 蛋白位于基底外侧膜。
代谢性酸中毒期间阴离子药物的肾排泄减少可能部分归因于 OAT3 蛋白水平降低。
