Kong Fandi, Pang Xiaoyan, Zhong Kan, Guo Zitao, Li Xiuli, Zhong Dafang, Chen Xiaoyan
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China
Drug Metab Dispos. 2017 Jun;45(6):593-603. doi: 10.1124/dmd.116.074492. Epub 2017 Mar 17.
Morinidazole is a 5-nitroimidazole drug. Its sulfate conjugate M7 was a sensitive substrate of organic anion transporter 1 (OAT1) and OAT3, whereas -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 IC values of 19.2, 87.4, and 222 M (M7); 8.53, 39.4, and 161 M (M8-1); and 6.75, 24.1, and 78.3 M (M8-2), respectively. In OAT1-overexpressed cells, CMPF, HA, and IS showed weak inhibition on M7 uptake with IC values of 187, 162, and 200 M, 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.
莫尼达唑是一种5-硝基咪唑类药物。其硫酸酯共轭物M7是有机阴离子转运体1（OAT1）和OAT3的敏感底物，而葡萄糖醛酸苷M8-1和M8-2仅是OAT3的底物。在慢性肾衰竭（CRF）患者中，这三种共轭物的血浆暴露量增加了15倍，本研究在5/6肾切除（5/6 Nx）大鼠中也发现了这一现象。尽管5/6 Nx大鼠肾脏中Oat1和Oat3的转录水平降低了50%，但在对照大鼠和5/6 Nx大鼠肾切片之间，三种共轭物的摄取未观察到差异。因此，5/6 Nx大鼠和人类体内高度升高的内源性尿毒症毒素，即3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）、马尿酸（HA）和硫酸吲哚酚（IS），被认为是影响因素。在大鼠肾切片中，HA和IS剂量依赖性地降低了M7、M8-1和M8-2的摄取，在5/6 Nx大鼠中其血浆浓度升高了5倍。在OAT3过表达细胞中，CMPF、HA和IS抑制了三种共轭物的摄取，M7的IC值分别为19.2、87.4和222 μM；M8-1的IC值分别为8.53、39.4和161 μM；M8-2的IC值分别为6.75、24.1和78.3 μM。在OAT1过表达细胞中，CMPF、HA和IS对M7摄取表现出较弱的抑制作用，IC值分别为187、162和200 μM。结果表明，CRF患者肾转运体mRNA表达降低可能不会影响这些转运体的活性。然而，累积的尿毒症毒素可能会抑制转运体，尤其是OAT3，导致相关底物的血浆暴露量发生变化。
