Research Paper

Pharmaceutical Research

, Volume 30, Issue 3, pp 847-856

First online:

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

  • Yoshiyuki KuboAffiliated withDepartment of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
  • , Yusuke KusagawaAffiliated withDepartment of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
  • , Masanori TachikawaAffiliated withDepartment of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of ToyamaDivision of Membrane Transport and Drug Targeting Graduate School of Pharmaceutical Sciences, Tohoku University
  • , Shin-ichi AkanumaAffiliated withDepartment of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
  • , Ken-ichi HosoyaAffiliated withDepartment of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama Email author 

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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.

KEY WORDS

inner blood-retinal barrier lipophilic basic drug organic cation transporter P-glycoprotein