Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects
Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects
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DOI：
10.1128/aac.03382-14
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发表时间：
2014-07
影响因子：
4.9
通讯作者：
Xiaoyan Pang;Yifan Zhang;Ruina Gao;Kan Zhong;D. Zhong;Xiaoyan Chen
中科院分区：
文献类型：
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作者：
Xiaoyan Pang;Yifan Zhang;Ruina Gao;Kan Zhong;D. Zhong;Xiaoyan Chen
摘要莫立硝唑是一种5-硝基咪唑类抗菌药物，在我国已被批准用于治疗阿米巴病、滴虫病和厌氧菌感染。据报道，奥硝唑（一种莫立硝唑类似物）与利福平或酮康唑联合给药后发生药物相互作用。因此，我们采用液相色谱-串联质谱法（LC-MS/MS）测定了中国健康志愿者服用利福平或酮康唑前后的血浆药代动力学（PK）。在暴露于600 mg利福平每日一次6天后，从时间0至时间t的浓度-时间曲线下面积（AUC 0-t）和血清中的最大浓度（Cmax）分别降低了28%和23%; N+-葡萄糖醛酸苷的Cmax增加了14%，而其AUC 0-ts几乎没有变化。200 mg酮康唑每日一次暴露7天后，母体药物的AUC 0-t和Cmax未受到显著影响。N+-葡萄糖醛酸苷的Cmax降低23%; AUC 0-ts降低14%。利福平或酮康唑联合给药后，硫酸盐结合物的暴露量几乎没有变化。利用重组UGT 1A 9酶和人肝细胞研究了莫硝唑及其代谢物药动学行为改变的机制。在人肝细胞中，酮康唑剂量依赖性地抑制N+-葡萄糖醛酸苷的形成（50%抑制浓度[IC 50]，1.5 μM），而利福平诱导UGT 1A 9的mRNA水平增加28%，UGT 1A 9的活性增加53%。总之，利福平和酮康唑对莫硝唑和N+-葡萄糖醛酸苷血浆暴露量的影响小于50%;因此，利福平和酮康唑对莫硝唑的药代动力学几乎没有临床意义。
ABSTRACT 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 (AUC0-t) and maximum concentration in serum (Cmax) of morinidazole were decreased by 28% and 23%, respectively, after 6 days of exposure to 600 mg of rifampin once daily; the Cmaxs of N+-glucuronides were increased by 14%, while their AUC0-ts were hardly changed. After 7 days of exposure to 200 mg of ketoconazole once daily, the AUC0-t and Cmax of the parent drug were not affected significantly. Cmaxs of N+-glucuronides were decreased by 23%; AUC0-ts 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 μM), 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+-glucuronide are less than 50%; therefore, rifampin and ketoconazole have little clinical significance in the pharmacokinetics of morinidazole.