Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins
Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins
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DOI：
10.1124/dmd.116.074492
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发表时间：
2017-06
影响因子：
3.9
通讯作者：
Fandi Kong;Xiaoyan Pang;Kan Zhong;Zi-tao Guo;Xiu-li Li;D. Zhong;Xiaoyan Chen
中科院分区：
文献类型：
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作者：
Fandi Kong;Xiaoyan Pang;Kan Zhong;Zi-tao Guo;Xiu-li Li;D. Zhong;Xiaoyan Chen
莫里硝唑是一种5-硝基咪唑类药物。其硫酸盐结合物M7是有机阴离子转运蛋白1(OAT1)和OAT3的敏感底物，而N+-葡萄糖醛酸苷M8-1和M8-2只是OAT3底物。在慢性肾功能衰竭(CRF)患者中，三种结合物的血浆暴露增加了15倍，在本研究中，5/6肾切除(5/6 NX)大鼠也发现了这一点。虽然5/6 NX大鼠肾脏中OAT1和OAT3的转录减少了50%，但对照组和5/6 NX大鼠肾脏切片的三种结合摄取没有差异。因此，5/6NX大鼠和人尿毒症内源性毒素，即3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)、马尿酸(HA)和吲哚硫酸盐(IS)是尿毒症的影响因素。在大鼠肾脏切片中，HA和IS可剂量依赖性地减少M7、M8-1和M8-2的摄取，其血浆浓度在5/6 NX大鼠中升高5倍。在OAT3过表达细胞中，CMPF、HA和IS可抑制这三种结合蛋白的摄取，IC50值分别为19.2、87.4和222μM(M7)；8.53、39.4和161μM(M8-1)；以及6.75、24.1和78.3μM(M8-2)。在OAT1过表达细胞中，CMPF、HA和IS对M7摄取的抑制作用较弱，IC50值分别为187、162和200μM。结果提示，CRF患者肾脏转运蛋白基因表达降低可能不影响其活性。然而，尿毒症毒素的积累可能会抑制转运蛋白，特别是OAT3，导致相关底物的血浆暴露改变。
Morinidazole is a 5-nitroimidazole drug. Its sulfate conjugate M7 was a sensitive substrate of organic anion transporter 1 (OAT1) and OAT3, whereas N+-glucuronides M8-1 and M8-2 were only OAT3 substrates. In chronic renal failure (CRF) patients, plasma exposures of the three conjugates increased by 15-fold, which were also found in 5/6 nephrectomized (5/6 Nx) rats in this study. Although the transcriptions of Oat1 and Oat3 in 5/6 Nx rat kidneys decreased by 50%, no difference was observed on the three conjugate uptakes between control and 5/6 Nx rat kidney slices. Thus, the highly elevated endogenous uremic toxins in 5/6 Nx rats and humans, namely, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), hippuric acid (HA), and indoxyl sulfate (IS), were considered as influential factors. In rat kidney slices, the uptake of M7, M8-1, and M8-2 was dose dependently reduced by HA and IS, whose plasma concentrations were elevated 5 times in 5/6 Nx rats. In OAT3-overexpressed cells, the three conjugate uptakes were inhibited by CMPF, HA, and IS with IC50 values of 19.2, 87.4, and 222 μM (M7); 8.53, 39.4, and 161 μM (M8-1); and 6.75, 24.1, and 78.3 μM (M8-2), respectively. In OAT1-overexpressed cells, CMPF, HA, and IS showed weak inhibition on M7 uptake with IC50 values of 187, 162, and 200 μM, correspondingly. Results suggest that the reduced mRNA expression of renal transporters in CRF patients may not influence the activities of these transporters. However, accumulated uremic toxins may inhibit the transporters, particularly OAT3, leading to plasma exposure changes of relevant substrates.