慢性肾脏病（CKD）改变碳青霉烯类抗菌药物体内药动学行为，但机制不清也缺少临床剂量调整依据。我们研究和文献报道发现，CKD时体内蓄积尿毒症毒素抑制转运体和代谢酶活性，除了肾小球滤过及肾脱氢肽酶（DHP-I）代谢，肾脏有机阴离子转运体（OATs）介导的肾小管分泌也是影响该类药物体内清除重要因素。我们提出，结合药物体外OATs/DHP-I动力学参数和体内尿毒症毒素浓度，可以较准确地预测药物体内清除率、血浆和组织暴露水平。本项目以美罗培南和比阿培南为模型药，采用hOAT1、hOAT3-HEK293转染细胞摄取、DHP-I体外代谢、CKD大鼠体内PK实验，研究不同期CKD对药物清除的影响及机制，获得相关动力学参数；结合CKD患者PK研究，利用PBPK-PD模型和蒙特卡罗模拟，预测美罗培南和比阿培南不同给药方案在不同期CKD患者PK行为及可能达到的临床疗效，为碳青霉烯类药物给药方案调整提供新思路。

Chronic kidney disease (CKD) alters the pharmacokinetic of carbapenem antibacterial agents in vivo. However, the mechanism is unclear and the basis for clinical dosing adjustment is lacking. Literatures and our work suggest that accumulated uremic toxins in CKD patients could inhibit the activities of OATs and metabolic enzyme. In addition, other than the renal glomerular filtration and dehydropeptidase I (DHP-I) metabolism, kidney organic anion transporters (OATs) mediated renal tubular secretion is an important factor affecting the elimination of carbapenem. Therefore, we assume that combining the in vitro drug OATs/DHP-I kinetics parameters with concentration of uremic toxins in vivo can accurately predict drug clearance, exposure levels of plasma and organisms. In this study, meropenem and biapenem will be used as modeling drugs. Uptake assay in OAT1 and OAT3 stably transfected HEK293 cells, DHP-I metabolism assay, and PK study in CKD rats will be used to elucidate the effect and mechanism of CKD on drug elimination in different periods of CKD. In addition, relevant kinetic parameters will be obtained. Through PK study in CKD patients, PBPK-PD modeling and Monte Carlo simulation, the PK process and the clinical efficacy of meropenem and biapenem in CKD patients will be predicted, which will provide a novel approach for dosing regimens.