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Impact of P-glycoprotein on blood-retinal barrier permeability: comparison of blood-aqueous humor and blood-brain barrier using mdr1a knockout rats.

Authors: Fujii, S  Setoguchi, C  Kawazu, K  Hosoya, K 
Citation: Fujii S, etal., Invest Ophthalmol Vis Sci. 2014 Jul 1;55(7):4650-8. doi: 10.1167/iovs.13-13819.
Pubmed: (View Article at PubMed) PMID:24985475
DOI: Full-text: DOI:10.1167/iovs.13-13819

PURPOSE: The purpose of this study was to clarify the impact of P-glycoprotein (P-gp) on blood-retinal barrier (BRB) and blood-aqueous humor barrier (BAB) permeability, in contrast to blood-brain barrier (BBB) permeability. METHODS: Permeabilities of six compounds, including P-gp substrates (quinidine, digoxin, and verapamil), were investigated in wild-type and mdr1a knockout rats using retinal, aqueous humor, and brain uptake index (RUI, AHUI, and BUI, respectively) methods and integration plot analysis. RESULTS: In both rat strains, quinidine, digoxin, and verapamil were transported by P-gp across each barrier; however, the impact of P-gp on retinal uptake of quinidine and verapamil was less pronounced than that on brain uptake. The apparent influx permeability clearance (Kin) values of verapamil in retina obtained from wild-type and knockout rats were similar (0.824 +/- 0.201 and 0.849 +/- 0.980 mL/min.g retina, respectively; mean +/- SD; n = 3 rats). The Kin in aqueous humor and brain obtained from knockout rats was, respectively, 3-fold and 12-fold higher than that of wild-type (P < 0.05). In P-gp-deficient conditions, the RUI and AHUI of quinidine, digoxin, and verapamil, as well as the BUI of quinidine and digoxin, were decreased by P-gp inhibitors. However, the BUI of verapamil was not changed by P-gp inhibitors. Results suggest that carrier-mediated influx transporters exist in the blood-ocular barriers and that the function of verapamil influx transporters is markedly different between the retina and brain. CONCLUSIONS: In both rat strains, P-gp operates in the blood-ocular barriers, and the impact of P-gp on BRB permeability to quinidine and verapamil is lower than that on BBB permeability.

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CRRD Object Information
CRRD ID: 11062172
Created: 2016-04-27
Species: All species
Last Modified: 2016-04-27
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.