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

Blessy George,

• Wen, Xia, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States

Xia Wen,

• Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States

Edgar A. Jaimes,

• Joy, Melanie S., University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States

Melanie S. Joy,

• Aleksunes, Lauren, Rutgers The State University of New Jersey, Piscataway, New Jersey, United States

Lauren Aleksunes,

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