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

• Published in: Pharmaceutical research 2013-03, Vol.30 (3), p.847-856
• Main Authors: Kubo, Yoshiyuki, Kusagawa, Yusuke, Tachikawa, Masanori, Akanuma, Shin-ichi, Hosoya, Ken-ichi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - metabolism; Biochemistry; Biological and medical sciences; Biological Transport; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-Retinal Barrier - metabolism; Cations - metabolism; Cell Line; General pharmacology; Glycoproteins; Male; Medical Law; Medical sciences; Organic Cation Transport Proteins - metabolism; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Pyrilamine - metabolism; Rats; Rats, Wistar; Research Paper; Retina; Vasodilator Agents - metabolism; Verapamil - metabolism
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-012-0926-y

Purpose To clarify the transport and inhibition characteristics involved in verapamil transport across the inner blood-retinal barrier (inner BRB). Methods The transport of [ 3 H]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 [ 3 H]verapamil was 614 μL/(min·g retina), which is 4.7-fold greater than that of brain. The retinal uptake of [ 3 H]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 [ 3 H]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.