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Involvement of a Novel Organic Cation Transporter in Verapamil Transport Across the Inner Blood-Retinal Barrier

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Abstract

Purpose

To clarify the transport and inhibition characteristics involved in verapamil transport across the inner blood-retinal barrier (inner BRB).

Methods

The transport of [3H]verapamil across the inner BRB was investigated using retinal uptake index and integration plot analyses in rats. The detailed transport characteristics were studied using TR-iBRB2 cells, a conditionally immortalized rat retinal capillary endothelial cell line that is an in vitro model of the inner BRB.

Results

The apparent influx permeability clearance of [3H]verapamil was 614 μL/(min·g retina), which is 4.7-fold greater than that of brain. The retinal uptake of [3H]verapamil was slightly increased by 3 mM verapamil and 10 mM qunidine and inhibited by 40 mM pyrilamine, supporting the carrier-mediated efflux and influx transport of verapamil across the inner BRB. TR-iBRB2 cells exhibited a concentration-dependent uptake of [3H]verapamil with a K m of 61.9 μM, and the uptake was inhibited by several cations, such as pyrilamine, exhibiting a different profile from the identified transporters. These transport properties suggest that verapamil transport at the inner BRB takes place via a novel organic cation transporter.

Conclusions

Our findings suggest that a novel organic cation transporter is involved in verapamil transport from the blood to the retina across the inner BRB.

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to thank Kowa Co., Ltd. for providing nipradilol. The present study was supported, in part, by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), Health and Welfare Department of Toyama Prefectural Government (Toyama, Japan), and Mochida Memorial Foundation (Tokyo, Japan).

Y. Kubo and Y. Kusagawa contributed equally to this work.

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Authors and Affiliations

  1. Department of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630, Sugitani, Toyama, 930-0194, Japan

    Yoshiyuki Kubo, Yusuke Kusagawa, Masanori Tachikawa, Shin-ichi Akanuma & Ken-ichi Hosoya

  2. Division of Membrane Transport and Drug Targeting Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Masanori Tachikawa

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  1. Yoshiyuki Kubo
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  2. Yusuke Kusagawa
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  3. Masanori Tachikawa
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  4. Shin-ichi Akanuma
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  5. Ken-ichi Hosoya
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Correspondence to Ken-ichi Hosoya.

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Kubo, Y., Kusagawa, Y., Tachikawa, M. et al. Involvement of a Novel Organic Cation Transporter in Verapamil Transport Across the Inner Blood-Retinal Barrier. Pharm Res 30, 847–856 (2013). https://doi.org/10.1007/s11095-012-0926-y

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