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Kidney Week

Abstract: PO0209

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • George, Blessy, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
  • Wen, Xia, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Joy, Melanie S., University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States
  • Aleksunes, Lauren, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States
Background

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) regulate the renal secretion of drugs including metformin, cisplatin, and entecavir. Studies suggest that ondansetron, an antiemetic drug and 5-HT3 antagonist, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test five structurally similar 5-HT3 antagonist drugs for their ability to inhibit the OCT2 and MATE1 transporters.

Methods

Transport of the fluorescent prototypical cation ASP+ (25 μM) was assessed in the presence and absence of 5-HT3 antagonists (0.5-20 μM) using two in vitro models: 1) HEK293 kidney cells overexpressing human OCT2 or MATE1 and 2) double-transfected hOCT2-MATE1 MDCK cells. Cimetidine (50 μM) was included as a positive control.

Results

The relative order of potency for inhibition of ASP+ uptake by OCT2 was palonosetron > ondansetron > granisetron > tropisetron > dolasetron and by MATE1 was ondansetron > palonosetron = tropisetron > granisetron > dolasetron. In hOCT2-MATE1 MDCK cells, ondansetron (0.5-20 μM) inhibited the transcellular transport of ASP+ up to 64%. Palonosetron, tropisetron, and dolasetron (10 and 20 μM) reduced the transcellular transport of ASP+ up to 80-90%. Granisetron did not alter the transcellular transport of ASP+ at concentrations up to 20 μM.

Conclusion

5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs resulting in potential drug-drug interactions. These data could have important implications for drug-induced kidney injury since 5-HT3 antagonists are routinely prescribed with the highly emetogenic and nephrotoxic chemotherapeutic drug cisplatin. Funded by NIH GM123330, ES005022, ES007148, CA072720, and CA046934.

Inhibition of OCT2-MATE1 Secretion of ASP+ by Ondansetron in MDCK Cells

Funding

  • Other NIH Support