Effects of antibiotics on the pharmacokinetics of indoxyl sulfate, a nephro-cardiovascular toxin

Abstract

1. 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.

2. 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.

3. The results showed that ciprofloxacin significantly increased AUC_0-t and T_1/2 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.

4. 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.

Keywords:

• Organic anion transporter
• indoxyl sulfate
• ciprofloxacin
• cephalosporins
• HEK293

Disclosure statement

The authors have no conflict of interests to disclose in relation to this article.

Additional information

Funding

The work was, in part, supported by the Ministry of Science and Technology, Taipei, Taiwan, ROC. (MOST 106-2320-B-039-009 and MOST 107-2320-B-039-044), China Medical University, Taichung, Taiwan, ROC. (CMU107-S-07) and China Medical University Hospital, Taichung, Taiwan, ROC. (DMR-106-138, DMR-107-139, DMR-108-146).