Piperacillin enhances the inhibitory effect of tazobactam on β-lactamase through inhibition of organic anion transporter 1/3 in rats  

作　　者：Shilei Yang Zhihao Liu Changyuan Wang Shijie Wen Qiang Meng Xiaokui Huo Huijun Sun Xiaodong Ma Jinyong Peng Zhonggui He Kexin Liu 

机构地区：[1]Department of Clinical Pharmacology,College of Pharmacy,Dalian Medical University,Dalian 116044,China [2]Provincial Key Laboratory for Pharmacokinetics and Transport,Dalian Medical University,Dalian 116044,China [3]Department of pharmacy,First Affiliated Hospital of Dalian Medical University,Dalian 116044,China [4]Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [5]College(Institute)of Integrative Medicine,Dalian Medical University,Dalian 116044,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2019年第6期677-686,共10页亚洲药物制剂科学（英文）

基　　金：supported by the National Natural Science Foundation of China(Nos.81874324,81473280,U1608283,81603186)

摘　　要：To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam,renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats.A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions.Renal slices were taken to examine the uptake of piperacillin and tazobactam.Pharmacokinetic studies ofβ-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam onβ-lactamase.The AUC(from 2.93±0.58 to 6.52±1.44 mg·min/ml)and the plasma clearance(CL P)(from 2.41±1.20 to 0.961±0.212 ml/min/kg)of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats.The renal clearance(CL R)of tazobactam decreased from 1.30±0.50 to 0.361±0.043 ml/min/kg.In summary,there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3.Piperacillin enhances the inhibitory effect of tazobactam onβ-lactamase through the inhibition of rOat1 and rOat3 in rats.The contribution rate of rOat1/3 for the synergistic effect was 20%when the two drugs were coadministered.To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam, renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats. A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions. Renal slices were taken to examine the uptake of piperacillin and tazobactam. Pharmacokinetic studies of β-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam on β-lactamase. The AUC(from 2.93 ± 0.58 to 6.52 ± 1.44 mg ·min/ml) and the plasma clearance( CL P)(from 2.41 ± 1.20 to 0.961 ± 0.212 ml/min/kg) of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats. The renal clearance( CL R) of tazobactam decreased from 1.30 ± 0.50 to 0.361 ± 0.043 ml/min/kg. In summary, there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3. Piperacillin enhances the inhibitory effect of tazobactam on β-lactamase through the inhibition of rOat1 and rOat3 in rats. The contribution rate of rOat1/3 for the synergistic effect was 20% when the two drugs were coadministered.

关 键 词：Organic ANION TRANSPORTER PIPERACILLIN TAZOBACTAM Drug-drug interaction 

分 类 号：R97[医药卫生—药品]