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Updated: Feb 5, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity
Dong Guo1, Hong Yang1, Qing Li2
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Pharmacy Hall N519, Baltimore, MD, 21201, USA.
Purpose:
The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common.
Methods:
The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice.
Results:
Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC50: 3.6 μM for human OCT2, 103 μM for human MATE1 and 202 μM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney.
Conclusions:
Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.
Insights
Carvedilol selectively inhibits organic cation transporters (OCTs), reducing cisplatin accumulation and protecting against kidney damage. This finding offers a potential strategy to mitigate cisplatin-induced nephrotoxicity.
Area of Science:
- Pharmacology
- Nephrology
- Molecular Biology
Background:
- Organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) influence renal drug elimination and toxicity.
- Cisplatin-induced nephrotoxicity is a common clinical challenge associated with cationic drugs.
Purpose of the Study:
- To identify selective OCT inhibitors over MATEs.
- To evaluate the protective potential of selective OCT inhibitors against cisplatin nephrotoxicity.
Main Methods:
- Screening of 41 drugs for OCT and MATE inhibition using metformin uptake assays in HEK293 cells and mouse models.
- Assessing the effects of carvedilol on transporter-mediated accumulation and cisplatin toxicity in vitro and in vivo.
Main Results:
- Five selective OCT inhibitors were identified; carvedilol demonstrated high selectivity for OCTs over MATEs.
- Carvedilol significantly reduced cisplatin accumulation and ameliorated its toxicity in both cellular and mouse models.
- In vitro IC50 values for carvedilol were 3.6 μM (hOCT2), 103 μM (hMATE1), and 202 μM (hMATE2-K).
Conclusions:
- Selective OCT inhibition by carvedilol may prevent cisplatin nephrotoxicity by limiting cellular entry via OCTs.
- This approach spares cisplatin elimination through MATEs, suggesting a targeted therapeutic strategy.
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