Involvement of a Novel Organic Cation Transporter in Verapamil Transport Across the Inner Blood-Retinal Barrier
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
To clarify the transport and inhibition characteristics involved in verapamil transport across the inner blood-retinal barrier (inner BRB).
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.
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.
Our findings suggest that a novel organic cation transporter is involved in verapamil transport from the blood to the retina across the inner BRB.
- Cunha-Vaz JG. The blood-retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res. 2004;78:715–21. CrossRef
- Stewart PA, Tuor UI. Blood-eye barriers in the rat: correlation of ultrastructure with function. J Comp Neurol. 1994;340:566–76. CrossRef
- Hosoya K, Tomi M, Tachikawa M. Strategies for therapy of retinal diseases using systemic drug delivery: relevance of transporters at the blood-retinal barrier. Expert Opin Drug Deliv. 2011;8:1571–87. CrossRef
- Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Ultracytochemical localization of the erythrocyte/HepG2-type glucose transporter (GLUT1) in cells of the blood-retinal barrier in the rat. Invest Ophthalmol Vis Sci. 1992;33:377–83.
- Hosoya K, Kondo T, Tomi M, Takanaga H, Ohtsuki S, Terasaki T. MCT1-mediated transport of L-lactic acid at the inner blood-retinal barrier: a possible route for delivery of monocarboxylic acid drugs to the retina. Pharm Res. 2001;18:1669–76. CrossRef
- Tomi M, Mori M, Tachikawa M, Katayama K, Terasaki T, Hosoya K. L-type amino acid transporter 1-mediated L-leucine transport at the inner blood-retinal barrier. Invest Ophthalmol Vis Sci. 2005;46:2522–30. CrossRef
- Tachikawa M, Takeda Y, Tomi M, Hosoya K. Involvement of OCTN2 in the transport of acetyl-L-carnitine across the inner blood-retinal barrier. Invest Ophthalmol Vis Sci. 2010;51:430–6. CrossRef
- Ohkura Y, Akanuma S, Tachikawa M, Hosoya K. Blood-to-retina transport of biotin via Na + -dependent multivitamin transporter (SMVT) at the inner blood-retinal barrier. Exp Eye Res. 2010;91:387–92. CrossRef
- Hosoya K, Makihara A, Tsujikawa Y, Yoneyama D, Mori S, Terasaki T, et al. Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercaptopurine. J Pharmacol Exp Ther. 2009;329:87–93. CrossRef
- Tomi M, Hosoya K. Application of magnetically isolated rat retinal vascular endothelial cells for the determination of transporter gene expression levels at the inner blood-retinal barrier. J Neurochem. 2004;91:1244–8. CrossRef
- Tagami M, Kusuhara S, Honda S, Tsukahara Y, Negi A. Expression of ATP-binding cassette transporters at the inner blood-retinal barrier in a neonatal mouse model of oxygen-induced retinopathy. Brain Res. 2009;1283:186–93. CrossRef
- Shen J, Cross ST, Tang-Liu DD, Welty DF. Evaluation of an immortalized retinal endothelial cell line as an in vitro model for drug transport studies across the blood-retinal barrier. Pharm Res. 2003;20:1357–63. CrossRef
- Kennedy BG, Mangini NJ. P-glycoprotein expression in human retinal pigment epithelium. Mol Vis. 2002;8:422–30.
- Kadam RS, Kompella UB. Influence of lipophilicity on drug partitioning into sclera, choroid-retinal pigment epithelium, retina, trabecular meshwork, and optic nerve. J Pharmacol Exp Ther. 2010;332:1107–20. CrossRef
- Toda R, Kawazu K, Oyabu M, Miyazaki T, Kiuchi Y. Comparison of drug permeabilities across the blood-retinal barrier, blood-aqueous humor barrier, and blood-brain barrier. J Pharm Sci. 2011;100:3904–11. CrossRef
- Hosoya K, Yamamoto A, Akanuma S, Tachikawa M. Lipophilicity and transporter influence on blood-retinal barrier permeability: a comparison with blood-brain barrier permeability. Pharm Res. 2010;27:2715–24. CrossRef
- Bankstahl JP, Kuntner C, Abrahim A, Karch R, Stanek J, Wanek T, et al. Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET. J Nucl Med. 2008;49:1328–35. CrossRef
- Tsuji A, Terasaki T, Takabatake Y, Tenda Y, Tamai I, Yamashima T, et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 1992;51:1427–37. CrossRef
- Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96:1698–705. CrossRef
- Han YH, Sweet DH, Hu DN, Pritchard JB. Characterization of a novel cationic drug transporter in human retinal pigment epithelial cells. J Pharmacol Exp Ther. 2001;296:450–7.
- Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens. 2011;13:687–9. CrossRef
- Araie M, Mayama C. Use of calcium channel blockers for glaucoma. Prog Retin Eye Res. 2011;30:54–71. CrossRef
- Kubo Y, Fukui E, Akanuma S, Tachikawa M, Hosoya K. Application of membrane permeability evaluated in in vitro analyses to estimate blood-retinal barrier permeability. J Pharm Sci. 2012;101:2596–605. CrossRef
- Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Ueda M, Yanai N, et al. Conditionally immortalized retinal capillary endothelial cell lines (TR-iBRB) expressing differentiated endothelial cell functions derived from a transgenic rat. Exp Eye Res. 2001;72:163–72. CrossRef
- Hosoya K, Tomi M. Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functions. Biol Pharm Bull. 2005;28:1–8. CrossRef
- Hosoya K, Minamizono A, Katayama K, Terasaki T, Tomi M. Vitamin C transport in oxidized form across the rat blood-retinal barrier. Invest Ophthalmol Vis Sci. 2004;45:1232–39. CrossRef
- Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K, et al. The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab. 2002;22:1327–35. CrossRef
- Alm A, Törnquist P. The uptake index method applied to studies on the blood-retinal barrier. I. A methodological study. Acta Physiol Scand. 1981;113:73–9. CrossRef
- Pardridge WM, Fierer G. Blood-brain barrier transport of butanol and water relative to N-isopropyl-p-iodoamphetamine as the internal reference. J Cereb Blood Flow Metab. 1985;5:275–81. CrossRef
- Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (MULTI) for microcomputer. J Pharmacobiodyn. 1981;4:879–85. CrossRef
- Suzuki T, Ohmuro A, Miyata M, Furuishi T, Hidaka S, Kugawa F, et al. Involvement of an influx transporter in the blood-brain barrier transport of naloxone. Biopharm Drug Dispos. 2010;31:243–52.
- Yamazaki M, Terasaki T, Yoshioka K, Nagata O, Kato H, Ito Y, et al. Carrier-mediated transport of H1-antagonist at the blood-brain barrier: a common transport system of H1-antagonists and lipophilic basic drugs. Pharm Res. 1994;11:1516–8. CrossRef
- Okura T, Hattori A, Takano Y, Sato T, Hammarlund-Udenaes M, Terasaki T, et al. Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone. Drug Metab Dispos. 2008;36:2005–13. CrossRef
- Murakami H, Sawada N, Koyabu N, Ohtani H, Sawada Y. Characteristics of choline transport across the blood-brain barrier in mice: correlation with in vitro data. Pharm Res. 2000;17:1526–30. CrossRef
- Karlsson C, Mäepea O, Alm A. Choline transport through the blood-retinal and the blood-brain barrier in vivo. Acta Ophthalmol (Copenh). 1984;62:763–6. CrossRef
- Tomi M, Arai K, Tachikawa M, Hosoya K. Na+-independent choline transport in rat retinal capillary endothelial cells. Neurochem Res. 2007;32:1833–42. CrossRef
- Zhang N, Kannan R, Okamoto CT, Ryan SJ, Lee VH, Hinton DR. Characterization of brimonidine transport in retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2006;47:287–94. CrossRef
- Mizuno K, Koide T, Yoshimura M, Araie M. Neuroprotective effect and intraocular penetration of nipradilol, a beta-blocker with nitric oxide donative action. Invest Ophthalmol Vis Sci. 2001;42:688–94.
- Arthur S, Cantor LB. Update on the role of alpha-agonists in glaucoma management. Exp Eye Res. 2011;93:271–83. CrossRef
- Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez MF. Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J Neuropsychiatry Clin Neurosci. 2010;22(1):8–18. CrossRef
- Ristori C, Filippi L, Dal Monte M, Martini D, Cammalleri M, Fortunato P, et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade. Invest Ophthalmol Vis Sci. 2011;52:155–70. CrossRef
- Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H. Drug excretion mediated by a new prototype of polyspecific transporter. Nature. 1994;372:549–52. CrossRef
- Urakami Y, Okuda M, Masuda S, Saito H, Inui K. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther. 1998;287:800–5.
- Gründemann D, Babin-Ebell J, Martel F, Ording N, Schmidt A, Schömig E. Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells. J Biol Chem. 1997;272:10408–13. CrossRef
- Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, et al. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem. 1998;273:15971–9. CrossRef
- Wu X, George RL, Huang W, Wang H, Conway SJ, Leibach FH, et al. Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta. 2000;1466:315–27. CrossRef
- Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M, et al. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999;289:768–73.
- Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, et al. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther. 1999;290:1482–92.
- Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, et al. Na+-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999;291:778–84.
- Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A. 2005;102:17923–8. CrossRef
- Ohta KY, Inoue K, Hayashi Y, Yuasa H. Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006;34:1868–74. CrossRef
- Engel K, Wang J. Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol. 2005;68:1397–407. CrossRef
- Involvement of a Novel Organic Cation Transporter in Verapamil Transport Across the Inner Blood-Retinal Barrier
Volume 30, Issue 3 , pp 847-856
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- inner blood-retinal barrier
- lipophilic basic drug
- organic cation transporter
- Industry Sectors
- Author Affiliations
- 1. Department of Pharmaceutics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630, Sugitani, Toyama, 930-0194, Japan
- 2. Division of Membrane Transport and Drug Targeting Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan