Impact of P-Glycoprotein on Blood–Retinal Barrier Permeability: Comparison of Blood–Aqueous Humor and Blood–Brain Barrier Using<i>Mdr1a</i>Knockout Rats

Fujii, Shinobu; Setoguchi, Chikako; Kawazu, Kouichi; Hosoya, Ken‐ichi

doi:10.1167/iovs.13-13819

Cited by 29 publications

(33 citation statements)

References 46 publications

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“…In the in vivo inhibition study of [ 3 H] verapamil transport, the RUI was significantly reduced in the presence of pyrilamine, a cationic drug, whereas the BUI was increased by pyrilamine. 21) In the further assessment of differences in the BRB and BBB, a study with P-gp knockout rats showed the negligible impact of P-gp on K in, verapamil, retina in spite of a marked alteration of the K in, verapamil, brain 22) ; similar results were reported in a study using P-gp/Bcrp knockout mice. 23) These findings strongly support differences in transport properties of the BRB and BBB, and suggest the dominant influx transport of verapamil at the BRB (Fig.…”

Section: Cationic Drug Transport At the Brbsupporting

confidence: 65%

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

Kubo

Akanuma

Hosoya

2017

Biological & Pharmaceutical Bulletin

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The retina is a tissue essential for vision, and the blood-retina barrier (BRB) helps to maintain an optimal microenvironment for the neural system in the retina. Recent findings concerning the BRB showed the involvement of transporters at the inner and outer BRB in drug and nutrient transport, suggesting their utility in the development of novel drug delivery systems to the retina. An in vitro-in vivo relationship study of permeability suggested the influx transport of verapamil, a cationic drug, across the BRB, and further in vivo and in vitro studies of cationic drugs, such as verapamil, propranolol and clonidine, revealed the involvement of carrier-mediated process in their influx transport at the BRB. Studies on substrate specificity in TR-iBRB2 cells, an in vitro model cell line of the inner BRB, suggests the involvement of novel organic cation transporter in the influx transport of cationic drugs at the inner BRB. Considering the neuroprotective effect previously reported for several cationic drugs, such as propranolol and clonidine, the study of cation transport at the BRB is widely expected to improve the treatment of retinal diseases, such as diabetic retinopathy and age-related macular degeneration.

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Section: Cationic Drug Transport At the Brbsupporting

confidence: 65%

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

Kubo

Akanuma

Hosoya

2017

Biological & Pharmaceutical Bulletin

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“…The 6.3‐fold lower [ 3 H]‐verapamil ER B at the BRB as compared with the BBB also suggests that P‐gp efflux is less important at the retina. A previous study using P‐gp‐deficient rats to evaluate [ 3 H]‐verapamil distribution in the eye using the retinal uptake index method shows a similar 1.5‐fold ER B effect (Fujii et al ., ). In contrast to the BBB, chemical or physical Bcrp disruption was insufficient to reveal any impact on the ER B measured using [ 3 H]‐mitoxantrone in the whole retina.…”

Section: Discussionmentioning

confidence: 97%

Blood–brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P‐glycoprotein on a novel verapamil influx carrier

Chapy

Saubaméa

Tournier

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEThe respective impact and interplay between ABC (P-glycoprotein/P-gp/Abcb1a, BCRP/ABCG2, MRP/ABCC) and SLC transporter functions at the blood-brain barrier (BBB) and blood-retinal barriers (BRB) are incompletely understood. EXPERIMENTAL APPROACHWe measured the initial cerebral and retinal distribution of selected ABC substrates by in situ carotid perfusion using P-gp/Bcrp knockout mice and chemical ABC/SLC modulation strategies. P-gp, Bcrp, Mrp1 and Mrp4 were studied by confocal retina imaging. KEY RESULTSChemical or physical disruption of P-gp increased [ ]-zidovudine transport suggested, respectively, that Bcrp efflux was less involved at the BRB than BBB, whereas Mrps were significantly and similarly involved at both barriers. Confocal imaging showed that P-gp and Bcrp were expressed in intra-retinal vessels (inner BRB/iBRB) but absent from the blood/basal membrane of cells of the retinal pigment epithelium (outer BRB/oBRB/RPE) where, in contrast, Mrp1 and Mrp4 were localized. CONCLUSIONS AND IMPLICATIONSP-gp, Bcrp, Mrp1 and Mrp4 are differentially expressed at the outer and inner BRB, resulting in an altered ability to limit substrate distribution at the retina as compared with the BBB. [ 3 H]-Verapamil distribution is not P-gp-specific and involves a proton antiporter at both the BBB and BRB. However, this transport is concealed by P-gp at the BBB, but not at the BRB, where P-gp activity is reduced.

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“…The RUI and BUI of [ 3 H]pravastatin and [ 3 H]E17bG in wild-type rats were almost the same as those in Mdr1a knockout rats and were lower than the lipophilicity trend line (Fujii et al, 2014) (Fig. 1, A and B).…”

Section: Resultsmentioning

confidence: 76%

Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats

et al. 2015

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Systemically administered pravastatin effectively treats diabetic retinopathy without central nervous system side effects. The efflux transport mechanism of pravastatin from the brain has already been clarified. In this study, the influx of pravastatin across the bloodretinal and blood-brain barriers (BRB and BBB) and the efflux of pravastatin from the retina were investigated using rats. Pravastatin influx (blood-to-tissues) was assessed using the retinal and brain uptake index (RUI and BUI) methods, and microdialysis was performed to investigate the efflux (retina-to-blood) transport of pravastatin. The RUI and BUI values for [ 3 H]pravastatin were lower than those expected based on its lipophilicity, suggesting that the influx transport across the BRB and BBB was less than the reversedirection transport. The RUI and BUI values for [ 3 H]pravastatin were significantly decreased by pravastatin, digoxin, and probenecid, indicating that pravastatin undergoes carrier-mediated influx transport in the blood-to-tissues direction across the BRB and BBB. After intravitreal injection, [3 H]pravastatin and the bulk flow marker ]pravastatin during the terminal phase was 1.66-fold greater than that of [ 14 C]D-mannitol. Efflux transport was reduced in the retinal presence of pravastatin, digoxin, and benzylpenicillin, suggesting that pravastatin is transported via efflux transporters. In conclusion, pravastatin is transported across the BRB via uptake and efflux transporters in both the blood-to-retina and retina-to-blood directions, and the retina-to-blood transporters are dominant, based on the lower values of the RUI compared with the values expected from the lipophilicity IntroductionAlthough some statins have pharamacologic effects on diabetic retinopathy, as well as central nervous system (CNS) side effects, systemically administrated pravastatin reduces signs of diabetic retinopathy in diabetic patients and does not produce CNS side effects such as sleep disturbances (Gordon et al., 1991;Saheki et al., 1994).Generally, the permeability of drugs into the retina from the blood is strictly regulated by the blood-retinal barrier (BRB), which is analogous to the blood-brain barrier (BBB). The BRB consists of both retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial (RPE) cells (outer BRB), which together form the complex tight junctions that restrict paracellular solute transport. The control of the intraocular environment and the maintenance of neuroretinal homeostasis are mediated, in part, by the various transporters expressed at the BRB (Hosoya and Tomi, 2005).Pravastatin is a substrate of the organic anion transporting polypeptides1a4 (oatp2; slco1a4) and the organic anion transporter 3 (oat3; slc22a8) (Kikuchi et al., 2004). Oatp1a4 is localized to both the luminal and abluminal membranes of the inner BRB and on the apical membrane of RPE cells of rats (Akanuma et al., 2013), whereas oat3 is expressed on only the abluminal side of the rat inner BRB and is not found on RPE cells (Ho...

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Impact of P-Glycoprotein on Blood–Retinal Barrier Permeability: Comparison of Blood–Aqueous Humor and Blood–Brain Barrier UsingMdr1aKnockout Rats

Abstract: 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.

Cited by 29 publications

References 46 publications

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

Blood–brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P‐glycoprotein on a novel verapamil influx carrier

Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats

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