Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

Toxicol Appl Pharmacol. 2013 Nov 15;273(1):100-9. doi: 10.1016/j.taap.2013.08.024. Epub 2013 Aug 31.

Abstract

The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1-/- mice. The nephrotoxicity was assessed in the wild-type and Mate1-/- mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1-/- mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients.

Keywords: 5-HT(3); 5-Hydroxytryptamine-3; AUC; Area under curve; BUN; Blood urea nitrogen; Cisplatin; Drug interaction; HEK-293; Human MATE2 isoforms (specific in the kidney); Human embryonic kidney cell; Kidney injury molecular-1 protein; Kim-1; Lcn2; Lipocalin 2 gene; MATE1/2; MATE2-k; Multidrug and toxin extrusion 1/2; Multidrug and toxin extrusion protein; Nephrotoxicity; OCT2; Ondansetron; Organic cation transporter; Organic cation transporter 2; SNP; Single-nucleotide polymorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cisplatin / toxicity*
  • HEK293 Cells
  • Humans
  • Kidney / drug effects*
  • Kidney / pathology
  • Metformin / pharmacokinetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Ondansetron / toxicity*
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2
  • Serotonin 5-HT3 Receptor Antagonists / toxicity

Substances

  • MATE1 protein, human
  • MATE1 protein, mouse
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Serotonin 5-HT3 Receptor Antagonists
  • Slc22a2 protein, mouse
  • Ondansetron
  • Metformin
  • Cisplatin