Luo Shu-Shang, Yu Chung-Ping, Hsieh Yow-Wen, Chao Pei-Dawn Lee, Sweet Douglas H, Hou Yu-Chi, Lin Shiuan-Pey
School of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC.
Xenobiotica. 2020 May;50(5):588-592. doi: 10.1080/00498254.2019.1660433. Epub 2019 Sep 4.
Indoxyl sulfate (IS), a highly protein-bound nephro-cardiovascular toxin, was poorly removed by hemodialysis. IS exists as anions in the body and the renal excretion is mediated by organic anion transporter 1 (OAT1) and OAT3. Acidic antibiotics such as cephalosporins and fluoroquinolones were putative substrates/inhibitors of OATs. We hypothesized that cephalosporins and fluoroquinolones might compete with IS for OAT1- and/or OAT3-mediated renal excretions.This study investigated the effects of ciprofloxacin, cefuroxime, cefotaxime, cefazolin and ofloxacin on the intravenous pharmacokinetics of IS in rats. IS was intravenously injected with and without each individual antibiotics, and the concentrations of IS in serum and lysate were determined by HPLC.The results showed that ciprofloxacin significantly increased AUC and T of IS by 272% and 491%, respectively, and decreased the clearance by 71%. However, ofloxacin, cefuroxime, cefotaxime and cefazolin did not alter the pharmacokinetics of IS. Furthermore, cell line study showed that ciprofloxacin inhibited the OAT3-mediated transport of IS.This study indicates 30 mg/kg of ciprofloxacin decreased the clearance of IS through inhibition on the OAT3-mediated transport, whereas 50 mg/kg of ofloxacin, cefuroxime, cefotaxime and cefazolin did not show significant influence.
硫酸吲哚酚（IS）是一种与蛋白质高度结合的肾心血管毒素，血液透析对其清除效果不佳。IS在体内以阴离子形式存在，其肾脏排泄由有机阴离子转运体1（OAT1）和OAT3介导。酸性抗生素如头孢菌素和氟喹诺酮类被认为是OATs的底物/抑制剂。我们推测头孢菌素和氟喹诺酮类可能与IS竞争OAT1和/或OAT3介导的肾脏排泄。本研究考察了环丙沙星、头孢呋辛、头孢噻肟、头孢唑林和氧氟沙星对大鼠体内IS静脉药代动力学的影响。分别在单独给予和未给予每种抗生素的情况下静脉注射IS，采用高效液相色谱法测定血清和裂解物中IS的浓度。结果显示，环丙沙星使IS的AUC和t分别显著增加272%和491%，清除率降低71%。然而，氧氟沙星、头孢呋辛、头孢噻肟和头孢唑林并未改变IS的药代动力学。此外，细胞系研究表明环丙沙星抑制OAT3介导的IS转运。本研究表明，30mg/kg的环丙沙星通过抑制OAT3介导的转运降低了IS的清除率，而50mg/kg的氧氟沙星、头孢呋辛、头孢噻肟和头孢唑林未显示出显著影响。
