药物是急性肾损的重要诱因，极大的限制了药物的临床应用。亚胺培南/西司他丁是常用的复方抗菌制剂，尽管抗菌活性强大，其肾毒性在临床上仍无法完全避免。因此，非常有必要研究亚胺培南肾毒性的作用机制和防治靶点，开发更有效的防治策略。我们的前期研究首次证明，通过抑制有机阴离子转运体OATs和脱氢肽酶DHP-I，西司他丁明显降低亚胺培南肾毒性。本研究拟采用家兔和人原代肾小管上皮细胞体外培养及OATs转染细胞摄取和基因沉默等技术，建立体内体外药动学和肾毒性的相互作用关系，（1）阐明OATs和DHP-I介导的亚胺培南肾毒性的分子药代动力学机制；（2）以OATs和DHP-I为靶点，利用特异性荧光探针从中药中寻找双重抑制剂用于替代或联合西司他丁防治亚胺培南的肾毒性。本研究有利于深入认识 OATs 和 DHP-I 协同作用影响亚胺培南肾毒性的机制，还为中药应用于亚胺培南肾毒性的防治提供了新的科学的证据。

Drugs are associated frequently with the development of various types of acute kidney injury. Imipenem and cilastatin are used together in clinical with broad spectrum of antibacterial activity. Although well tolerated, Imipenem and cilastatin induce a rare but serious nephrotoxicity. It is therefore necessary to study the molecular mechanism and find a more efficient way to prevent imipenem nephrotoxicity. In our previous study, cilastatin was found, for the first time, to decrease the renal damage induced by imipenem via inhibition of both renal organic anion transporters (OATs) and organic anion transporters (DHP-I). The purposes of this study are (1) to further investigate the molecular pharmacokinetic mechanisms of imipenem nephrotoxicity related in OATs and DHP-I; (2) to develop potent inhibitors of OATs and DHP-I from traditional Chinese medicines (TCMs) using high throughput screening with fluorescent probes. The DDIs and the involved mechanisms are studied through in vivo rabbit pharmacokinetics study, in vitro uptake study using rabbit/human primary renal tubular epithelial cells and OATs transfected cells, and gene knockdown assays by siRNA. The results will clarify the roles of OATs and DHP-I on renal damage induced by imipenem and provided a new way of alleviating the nephrotoxicity of imipenem using TCMs.