吗啉硝唑是国内研制5-硝基咪唑类抗菌新药，其原型和主要代谢物（硫酸结合物M7、葡萄糖醛酸结合物M8-1和M8-2）主要经肾排泄。前期研究发现肾功能不全时代谢物肾脏消除受到影响，其机制尚不明确。ADMET Predictor模拟结果表明原型药和代谢物M5、M6在脑组织具有较高的分布，相关跨膜组分可能与药物中枢毒性相关。本项目拟采用LC-MS-MS方法作为检测手段、利用药物转运体基因转染技术、抑制剂干扰、PCR、Western blot等方法，通过体内、体外等手段观察OATs和MATEs等转运体对吗啉硝唑及代谢物肾脏排泄的影响；并采用体外血脑屏障模型和动物实验探索OATs与吗啉硝唑及代谢物血脑屏障转运的相关性。该研究成果对阐明硝基咪唑类药物的肾脏排泄机制以及药物相互作用的分子药代动力学机制具有重要的理论价值和临床意义。

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]). Renal excretion is the major elimination path of morinidazole and its major metabolites. Previous study revealed that patients with severe renal impairment exhibited lower renal clearance of the conjugated metabolites. Its mechanism remains poorly understood. The results of ADMET Predictor showed that the distribution of the parent and metabolite M5 and M6 were higher in the brain tissue, which may be relevant with its neurological toxicity. In our study, a rapid and selective liquid chromatographic/tandem mass spectrometric method has been developed to analyze the biological samples. We will employed the transfected cells, PCR and Western blot methods to determine the effects conducted by OATs and MATEs transporters in the excretion of morinidazole and its major metabolites. We also establish a blood-brain barrier and animal model for evaluating the effect of OATs on the disposition of morinidazole and its metabolisms in brain. The research has important theoretical and clinical significance to clarify the molecular pharmacokinetic mechanism of renal excretion and drug-drug interaction for morinidazole.