Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

doi:10.1128/AAC.02414-14

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	Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites
	Zhong, Kan; Li, Xiuli; Xie, Cen; Zhang, Yifan; Zhong, Dafang; Chen, Xiaoyan
刊名	ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
	2014-07
卷号	58 期号:7 页码:4153-4161
ISSN号	0066-4804
DOI	10.1128/AAC.02414-14
文献子类	Article
英文摘要	Morinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans via N+-glucuronidation (N+-glucuronide of S-morinidazole [M8-1] and N+-glucuronide of R-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively. In vitro transporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (K-m = 28.6 and 54.0 mu M, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.
资助项目	National Natural Science Foundation of China[81173115] ; National Natural Science Foundation of China[81173117]
WOS关键词	ORGANIC ANION TRANSPORTERS ; KIDNEY DRUG TRANSPORTERS ; EXPRESSION LEVELS ; N+-GLUCURONIDES ; PROTEIN BINDING ; FAILURE ; DISEASE ; SULFATE ; PLASMA ; OATS
WOS研究方向	Microbiology ; Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000338846500073
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276999]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Zhong, Kan,Li, Xiuli,Xie, Cen,et al. Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2014,58(7):4153-4161.
APA	Zhong, Kan,Li, Xiuli,Xie, Cen,Zhang, Yifan,Zhong, Dafang,&Chen, Xiaoyan.(2014).Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,58(7),4153-4161.
MLA	Zhong, Kan,et al."Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 58.7(2014):4153-4161.