Role of organic anion transporter 3 in the renal excretion of biapenem and potential drug-drug interactions
Role of organic anion transporter 3 in the renal excretion of biapenem and potential drug-drug interactions
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有机阴离子转运蛋白3在比阿培南肾排泄中的作用和潜在的药物相互作用
DOI：
10.1016/j.ejps.2021.105814
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发表时间：
2021-03-31
影响因子：
4.6
通讯作者：
Dong, Jing
中科院分区：
文献类型：
--
作者：
Li, Wenyan;Jiao, Zheng;Dong, Jing
Biapenem是一种碳青霉烯类抗生素。它主要以原型形式通过肾脏排泄。然而，比阿培南肾脏排泄的分子机制和潜在的药物相互作用（DDI）仍不清楚。本研究通过体外试验，评价了有机阴离子转运蛋白（OAT）1/3和有机阳离子转运蛋白（OCT）2在比阿培南肾脏排泄中的作用，以及比阿培南与6种临床常用抗生素和抗病毒药物（OAT 3的底物或抑制剂）的潜在药物间的药物不良反应。进一步探讨了丙磺舒对比阿培南在大鼠体内药代动力学的影响。我们观察到比阿培南不能抑制OAT 1或OCT 2的转运活性，而轻度抑制OAT 3（IC 50>500 μ M）。在所测试的抗生素和抗病毒药物中，发现哌拉西林、利奈唑胺和苄青霉素的DDI指数值（最大未结合血浆浓度超过IC 50，Imax，u/IC 50）相对较高，分别为2.84、1.7和0.62。虽然丙磺舒在体外的DDI指数最高（27.1），但在大鼠体内未观察到丙磺舒对比阿培南的药代动力学有显著影响。我们的结果表明，比阿培南主要通过肾小球滤过消除，而OAT 3介导的肾小管分泌是次要途径。比阿培南不是临床相关底物或抑制剂，因为其与OAT 3的亲和力较低。根据目前的结果，比阿培南与其他抗生素和抗病毒药物一起使用是安全的，这些药物作为OAT 3的底物或抑制剂。
Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro. Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC50 >500 mu M). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC50, Imax,u/IC50) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro, no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.