OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam

被引：53

作者：

Wen, Shijie ^{[1
,3
]}

Wang, Changyuan ^{[1
,2
]}

Duan, Yingjie ^{[4
]}

Huo, Xiaokui ^{[1
,2
]}

Meng, Qiang ^{[1
,2
]}

Liu, Zhihao ^{[1
,2
]}

Yang, Shilei ^{[1
]}

Zhu, Yanna ^{[1
]}

Sun, Huijun ^{[1
,2
]}

Ma, Xiaodong ^{[1
,2
]}

Yang, Siyun ^{[3
]}

Liu, Kexin ^{[1
,2
]}

机构：

[1] Dalian Med Univ, Coll Pharm, Dept Clin Pharmacol, 9 West Sect,Lvshun South Rd, Dalian 116044, Peoples R China

[2] Dalian Med Univ, Prov Key Lab Pharmacokinet & Transport, Dalian, Liaoning, Peoples R China

[3] Nanchong Cent Hosp, North Sichuan Med Coll, Clin Med Coll 2, Dept Clin Pharm, Nanchong, Peoples R China

[4] Fuxin Min Grp Co Ltd, Gen Hosp, Fuxin, Peoples R China

来源：

INTERNATIONAL JOURNAL OF PHARMACEUTICS | 2018年 / 537卷 / 1-2期

基金：

中国国家自然科学基金;

关键词：

Piperacillin/tazobactam; Beta-lactamase inhibitor; Transporter; Organic anion transporters; Drug-drug interaction; Kidney; BETA-LACTAMASE INHIBITORS; EX-VIVO STIMULATION; P-AMINOHIPPURATE; RENAL EXCRETION; PHARMACOKINETICS; METHOTREXATE; TRANSPORT; BESTATIN; TISSUE; DEXAMETHASONE;

D O I：

10.1016/j.ijpharm.2017.12.037

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

This study aimed to demonstrate that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between piperacillin and tazobactam. After co-administration with piperacillin in rats, the AUC of tazobactam in plasma was significantly increased, and t(1/2 beta) was prolonged with significant reduction in plasma clearance, renal clearance and cumulative urinary excretion. In rat and human kidney slices, probenecid, p-aminohippurate and benzylpenicillin inhibited the uptake of piperacillin and tazobactam. Piperacillin significantly inhibited the uptake of tazobactam. Moreover, the uptakes of piperacillin, tazobactam and sulbactam in hOAT1/3-HEK293 cells were significantly higher compared with mock-HEK293 cells, respectively. Piperacillin significantly inhibited the uptake of tazobactam in hOAT1/3-HEK293 cells. The K-m values of tazobactam (431 +/- 67 mu M for hOAT1, 377 +/- 63 mu M for hOAT3) were significantly higher than those of piperacillin (37 +/- 5 mu M for hOAT1, 172 +/- 28 mu M for hOAT3). This suggested that piperacillin has a stronger affinity to hOAT1/3 than tazobactam. Meanwhile, the Km values of tazobactam were increased in the presence of piperacillin with unchanged V-max. This indicated that piperacillin inhibited the uptake of tazobactam in a competitive manner. In conclusion, piperacillin and tazobactam are the substrates of hOAT1/3, and OAT1/3 mediate the DDI between piperacillin and tazobactam.

引用

页码：172 / 182

页数：11

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