Changes of drug pharmacokinetics mediated by downregulation of kidney organic cation transporters Mate1 and Oct2 in a rat model of hyperuricemia
Changes of drug pharmacokinetics mediated by downregulation of kidney organic cation transporters Mate1 and Oct2 in a rat model of hyperuricemia
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DOI：
10.1371/journal.pone.0214862
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发表时间：
2019-04-05
期刊：
影响因子：
3.7
通讯作者：
Tamai, Ikumi
中科院分区：
文献类型：
--
作者：
Nishizawa, Kei;Yoda, Noriaki;Tamai, Ikumi
研究了高尿酸血症对肾脏药物转运蛋白表达和几种底物药物的药代动力学的影响。我们首先通过10天联合给药氧酸（尿酸酶抑制剂）和腺嘌呤（尿酸的生物合成前体）建立了无明显慢性肾衰竭症状的高尿酸血症大鼠模型。这些高尿酸血症大鼠的血浆尿酸浓度高达6 mg/dL，与高尿酸血症人的血清尿酸水平相似，菊粉清除率几乎没有变化。高尿酸血症大鼠肾脏多药和毒素挤出1 （Mate1, Slc47a1）、有机阴离子转运蛋白1 （Oat1, Slc22a6）、有机阳离子转运蛋白2 （Oct2, Slc22a2）、尿酸转运蛋白1 （Urat1, Slc22a12）和肽转运蛋白1 (Pept1, Slc15a1) mRNA水平均显著降低。由于Oct2、Mate1和Oat1对肾脏药物消除很重要，我们接下来研究了它们的底物二甲双胍、头孢氨苄和肌酐的药代动力学是否被改变。血浆二甲双胍浓度不受影响，但其肾组织蓄积明显增加。头孢氨苄的血药浓度、肾组织蓄积及血肌酐浓度均升高。高尿酸血症大鼠肾脏Mate1蛋白表达降低。因此，尽管多种因素可能影响肾脏对这些药物的处理，但这些观察结果至少可以部分解释为小管细胞mate1介导的根尖外排和oct2介导的基底外侧摄取的下调。我们的研究结果表明，高尿酸血症可以改变作为Mate1和/或Oct2底物的药物的处置。
The effects of hyperuricemia on the expression of kidney drug transporters and on the pharmacokinetics of several substrate drugs were examined. We first established a rat model of hyperuricemia without marked symptoms of chronic kidney failure by 10-day co-administration of oxonic acid (uricase inhibitor) and adenine (biosynthetic precursor of uric acid). These hyperuricemic rats showed plasma uric acid concentrations of up to 6 mg/dL, which is similar to the serum uric acid level in hyperuricemic humans, with little change of inulin clearance. The mRNA levels of multidrug and toxin extrusion 1 (Mate1, Slc47a1), organic anion transporter 1 (Oat1, Slc22a6), organic cation transporter 2 (Oct2, Slc22a2), urate transporter 1 (Urat1, Slc22a12) and peptide transporter 1 (Pept1, Slc15a1) were significantly decreased in kidney of hyperuricemic rats. Since Oct2, Mate1 and Oat1 are important for renal drug elimination, we next investigated whether the pharmacokinetics of their substrates, metformin, cephalexin and creatinine, were altered. The plasma concentration of metformin was not affected, while its kidney tissue accumulation was significantly increased. The plasma concentration and kidney tissue accumulation of cephalexin and the plasma concentration of creatinine were also increased. Furthermore, the protein expression of kidney Mate1 was decreased in hyperuricemic rats. Accordingly, although multiple factors may influence renal handling of these drugs, these observations can be accounted for, at least in part, by downregulation of Mate1-mediated apical efflux from tubular cells and Oct2-mediated basolateral uptake. Our results suggest that hyperuricemia could alter the disposition of drugs that are substrates of Mate1 and/or Oct2.