Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects
文献类型：期刊论文
| 作者 | Pang, Xiaoyan; Zhang, Yifan ; Gao, Ruina; Zhong, Kan; Zhong, Dafang; Chen, Xiaoyan
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| 刊名 | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
 |
| 出版日期 | 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 |
| WOS记录号 | WOS:000344157500042 |
| 出版者 | AMER SOC MICROBIOLOGY |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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