Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins

doi:10.1124/dmd.116.074492

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	Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins
	Kong, Fandi 1,2; Pang, Xiaoyan 1; Zhong, Kan 1; Guo, Zitao 1; Li, Xiuli 1; Zhong, Dafang1,2 ; Chen, Xiaoyan1,2
刊名	DRUG METABOLISM AND DISPOSITION
	2017-06-01
卷号	45 期号:6 页码:593-603
ISSN号	0090-9556
DOI	10.1124/dmd.116.074492
文献子类	Article
英文摘要	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 mu M (M7); 8.53, 39.4, and 161 mu M(M8-1); and 6.75, 24.1, and 78.3 mu M (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 mu 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.
资助项目	Youth Innovation Promotion Association CAS[00000000]
WOS关键词	ORGANIC ANION TRANSPORTERS ; MASS-SPECTROMETRY ; DRUG TRANSPORTERS ; RAT-KIDNEY ; PHARMACOKINETICS ; SULFATE ; POTENT
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000405621700003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272628]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Kong, Fandi,Pang, Xiaoyan,Zhong, Kan,et al. Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins[J]. DRUG METABOLISM AND DISPOSITION,2017,45(6):593-603.
APA	Kong, Fandi.,Pang, Xiaoyan.,Zhong, Kan.,Guo, Zitao.,Li, Xiuli.,...&Chen, Xiaoyan.(2017).Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins.DRUG METABOLISM AND DISPOSITION,45(6),593-603.
MLA	Kong, Fandi,et al."Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins".DRUG METABOLISM AND DISPOSITION 45.6(2017):593-603.