转运体介导哌拉西林/他唑巴坦及亚胺培南/西司他丁发生增效减毒药物相互作用的分子药代动力学机制

The combination of piperacillin and tazobactam, as well as imipenem and cilastatin, are used widely in clinical for their broad spectrum of antibacterial activity. Traditionally, pharmacoenhancers tazobactam and cilastatin have been developed as bacterial β-lactamase inhibitor and human renal dehydropeptidase I (DHP-I) inhibitor, respectively, which are able to effectively inhibit the metabolism of piperacillin and imipenem and thus enhance the plasma concentration and prolong the dosing interval. For the first time, OAT1/3-mediated drug-drug interactions (DDIs) induced by the pharmacoenhancers were identified to modulate the pharmacokinetics of piperacillin and imipenem in our previous studies. The purposes of this study are (1) to investigate the drug-drug interactions (DDI) between these two combinations and clarify the molecular pharmacokinetic mechanism of DDI; (2) to identify the potential roles of the DDIs in alleviating the nephrotoxicity of imipenem. The DDIs and the involved mechanisms are studied through in vivo rat pharmacokinetics study, in situ rat kidney perfusion technique, in vitro uptake study using rat/human kidney slices, uptake studies and bi-directional transport assays using transporter gene transfected cells, MTT assay, qRT-PCR, Western blotting and gene knockdown assays by siRNA. The present study will provide a new insight on the pharmacoenhancement of tazobactam and cilastatin and suggest that health care professionals and consumers should be aware of the potential for transporter based DDI.

哌拉西林/他唑巴坦和亚胺培南/西司他丁是临床常用的抗菌复方制剂。传统的药理作用机制认为这两种复方制剂使用的药效增强剂他唑巴坦和西司他丁分别通过抑制细菌β-内酰胺酶和人肾脱氢肽酶I对哌拉西林和亚胺培南的水解，从而维持这两种抗生素的有效抗菌浓度。我们的前期工作首次发现他唑巴坦和西司他丁还可通过有机阴离子转运体介导的药物相互作用（DDI）调控哌拉西林和亚胺培南的药代动力学。本研究拟采用大鼠in vivo、人和大鼠新鲜肾切片及转运体基因转染细胞摄取和基因沉默等技术，拟阐明（1）转运体介导的DDI对这两种复方制剂体内过程影响的分子药代动力学机制；（2）该DDI促使西司他丁降低亚胺培南肾毒性的药代动力学机制。本研究通过新发现，从理论上首次对这两种复方制剂的传统药理作用机制进行药代动力学方面的补充；从应用上呼吁临床医药工作者重视转运体介导的DDI，以期提高临床安全合理联合用药水平。

本课题的目的是证明除了肾脱氢肽酶（DHP-I）外，他唑巴坦和西司他丁还可通过调节Oat1/3 的功能，从而改变哌拉西林和亚胺培南的药代动力学来促进抗菌效果，增效减毒。.本课题主要分为两大部分，第一部分：菌血症时Oat1/3介导哌拉西林/他唑巴坦的肾脏DDI研究；第二部分：西司他丁拮抗亚胺培南肾毒性的药动学机制研究。这两部分均按照申报时的计划预期完成。.一、菌血症时Oat1/3介导哌拉西林/他唑巴坦的肾脏DDI研究.该部分建立大鼠菌血症模型，采用in vitro肾切片发现正常和菌血症大鼠肾切片中哌拉西林均显著抑制他唑巴坦的摄取，证明该课题对传统的哌拉西林/他唑巴坦复方制剂药理作用机制进行了补充，从而达到可提高该复方制剂疗效的临床用药目的。研究首次发现Oat1/3介导哌拉西林和他唑巴坦之间有益的药物相互作用、肾脏是哌拉西林和他唑巴坦DDI的靶器官。Oat1/3对哌拉西林增强他唑巴坦抑制β-内酰胺酶活性的贡献率为20%。肾脏是柚皮苷与他唑巴坦发生DDI的靶器官，柚皮苷抑制他唑巴坦的肾脏排泄。.二、 OAT1/3介导亚胺培南与西司他丁的药物相互作用.该部分采用大鼠肾排泄实验、大鼠肾切片实验、OAT1/3-HEK293 转染细胞摄取实验、基因沉默技术、RT-qPCR以及Western blotting等实验，从体外和体内考察 OATs 介导的亚胺培南和西司他丁的DDI。首次发现亚胺培南和西司他丁是OAT1和OAT3的底物。除了 DHP-I ，OATs 也参与亚胺培南和西司他丁的DDI，并介导亚胺培南在肾小管上皮细胞中的蓄积，导致肾脏毒性的发生。研究首次发现亚胺培南肾毒性的本体是其肾毒性强的代谢产物，西司他丁不但可抑制DHP-I，还可通过抑制oat1和oat3抑制亚胺培南代谢产物的产生。研究结果解释了西司他丁拮抗亚胺培南肾毒性的部分原因。OATs 可以作为一个潜在的治疗靶点，通过对其调控，预防和减轻亚胺培南肾毒性。

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