Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

doi:10.1128/AAC.03382-14

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	Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects
	Pang, Xiaoyan; Zhang, Yifan; Gao, Ruina; Zhong, Kan; Zhong, Dafang; Chen, Xiaoyan
刊名	ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
	2014-10
卷号	58 期号:10 页码:5987-5993
ISSN号	0066-4804
DOI	10.1128/AAC.03382-14
文献子类	Article
英文摘要	Morinidazole, a 5-nitroimidazole antimicrobial drug, has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. It was reported that drug-drug interaction happened after the coadministration of ornidazole, an analog of morinidazole, and rifampin or ketoconazole. Therefore, we measured the plasma pharmacokinetics (PK) of morinidazole and its metabolites in the healthy Chinese volunteers prior to and following the administration of rifampin or ketoconazole using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the concentration-time curve from time 0 to time t (AUC(0-t)) and maximum concentration in serum (C-max) of morinidazole were decreased by 28% and 23%, respectively, after 6 days of exposure to 600 mg of rifampin once daily; the C(max)s of N+-glucuronides were increased by 14%, while their AUC(0-t)s were hardly changed. After 7 days of exposure to 200 mg of ketoconazole once daily, the AUC(0-t) and C-max of the parent drug were not affected significantly. C(max)s of N+-glucuronides were decreased by 23%; AUC(0-t)s were decreased by 14%. The exposure of sulfate conjugate was hardly changed after the coadministration of rifampin or ketoconazole. Using recombinant enzyme of UGT1A9 and human hepatocytes, the mechanism of the altered PK behaviors of morinidazole and its metabolites was investigated. In human hepatocytes, ketoconazole dose dependently inhibited the formation of N+-glucuronides (50% inhibitory concentration [IC50], 1.5 mu M), while rifampin induced the mRNA level of UGT1A9 by 28% and the activity of UGT1A9 by 53%. In conclusion, the effects of rifampin and ketoconazole on the plasma exposures of morinidazole and N+-glucuronides are less than 50%; therefore, rifampin and ketoconazole have little clinical significance in the pharmacokinetics of morinidazole.
WOS关键词	TANDEM MASS-SPECTROMETRY ; DRUG-DRUG INTERACTIONS ; N+-GLUCURONIDES ; HUMAN PLASMA ; INDUCTION ; PHARMACODYNAMICS ; ORNIDAZOLE ; ZIDOVUDINE ; WARFARIN
WOS研究方向	Microbiology ; Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000344157500042
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276876]
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	Pang, Xiaoyan,Zhang, Yifan,Gao, Ruina,et al. Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2014,58(10):5987-5993.
APA	Pang, Xiaoyan,Zhang, Yifan,Gao, Ruina,Zhong, Kan,Zhong, Dafang,&Chen, Xiaoyan.(2014).Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,58(10),5987-5993.
MLA	Pang, Xiaoyan,et al."Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 58.10(2014):5987-5993.