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Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity

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Abstract

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.

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Abbreviations

AUC:

Area under curve

Cmax :

The maximum concentration

DDI:

Drug-drug interaction

H&E staining:

Haematoxylin and Eosin staining

IC50 :

The half maximal inhibitory concentration

MATE:

Multidrug and toxin extrusions

MPP+ :

1-methyl-4-phenylpyridinium

OCT:

Organic cation transporters

T1/2 :

Half life

TEA:

Tetraethyl ammonium

Tmax :

Time of the maxium concentration

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Acknowledgments and Disclosures

The present study was supported by the National Institute of General Medical Sciences of the US National Institutes of Health (NIH) [R01GM099742] and by the US Food and Drug Administration (FDA) [U01FD004320]. Dr. Dong Guo is an M-CERSI Scholar (FDA 1U01FD005946). Dr. Yan Shu is a co-founder for and owns equity in Optivia Biotechnology.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Pharmacy Hall N519, Baltimore, MD, 21201, USA

    Dong Guo, Hong Yang, Hyo Jung Bae, Obinna Obianom, James E. Polli & Yan Shu

  2. Department of Clinical Pharmacology, Xiangya Hospital, Xiangya Medical School, Central South University, Hunan, 410007, China

    Qing Li & Yan Shu

  3. Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510140, China

    Sujuan Zeng & Yan Shu

  4. Department of Oral Maxillofacial Surgery, Xiangya Hospital, Xiangya Medical School, Central South University, Hunan, 410007, China

    Tong Su

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  1. Dong Guo
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  2. Hong Yang
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  3. Qing Li
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  7. Tong Su
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  8. James E. Polli
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  9. Yan Shu
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Contributions

Designed Research: Yan Shu, James E. polli, Dong Guo.

Performed Research: Dong Guo, Hong Yang, Qing Li, Hyo Jung Bae, Sujuan Zeng, Tong Su.

Analyzed Data: Dong Guo, Hong Yang, Qing Li, Hyo Jung Bae, Yan Shu.

Wrote Manuscript: Dong Guo, Yan Shu.

Corresponding author

Correspondence to Yan Shu.

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Guo, D., Yang, H., Li, Q. et al. Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity. Pharm Res 35, 204 (2018). https://doi.org/10.1007/s11095-018-2486-2

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