Application of microdialysis to evaluate the efflux transport of estradiol 17-β glucuronide across the rat blood–retinal barrier

Katayama, Kazunori; Ohshima, Yuki; Tomi, Masatoshi; Hosoya, Ken

doi:10.1016/j.jneumeth.2006.03.012

Cited by 24 publications

(22 citation statements)

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“…Moreover, the transport processes for organic anions at the inner BRB are physiologically important because hormones and neurotransmitters are mostly metabolized in the form of organic anions in the retina and need to undergo efflux transport from the retina to the circulating blood. We recently reported the use of a microdialysis method that showed that estradiol 17-␤ glucuronide undergoes efflux transport via organic anion transporter polypeptide (oatp) 1a4 (Slco1a4; oatp2) at the BRB (Katayama et al, 2006).…”

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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

Hosoya

Makihara

Tsujikawa

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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The purpose of the present study was to characterize rat organic anion transporter (Oat) 3 (Oat3, Slc22a8) in the efflux transport at the inner blood-retinal barrier (BRB). Reverse transcription-polymerase chain reaction analysis showed that rat (r) Oat3 mRNA is expressed in retinal vascular endothelial cells (RVECs), but not rOat1 and rOat2 mRNA. The expression of Oat3 in the retina and human cultured retinal endothelial cells was further confirmed by Western blot analysis. Immunohistochemical staining in RVECs showed that rOat3 is colocalized with glucose transporter 1, but not P-glycoprotein, suggesting that rOat3 is possibly located at the abluminal membrane of the RVEC.

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“…The in vivo efflux transport of anionic drugs was characterized using microdialysis (Katayama et al, 2006). The expression and localization of Oat3 at the inner BRB was determined by reverse transcription (RT)-polymerase chain reaction (PCR), Western blot, and immunohistochemical analyses.…”

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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

Hosoya

Makihara

Tsujikawa

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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“…Pravastatin influx (blood-to-tissues) was assessed using the retinal uptake index (RUI) and compared with that of the BBB, and microdialysis was performed to investigate efflux (retina-to-blood) transport of pravastatin. In addition, estradiol 17-b glucuronide (E17bG) influx was evaluated as a model substrate of oatp1a4 and oat3 because the efflux mechanism of E17bG has already been clarified; that is, E17bG is transported from the vitreous humor to the blood via at least oatp1a4 (Katayama et al, 2006) and from the brain to blood via the oat family (mainly oat3) and oatp1a4 (Sugiyama et al, 2001 ABBREVIATIONS: ABC, ATP-binding cassette; BBB, blood-brain barrier; Bcrp, breast cancer resistance protein; BRB, blood-retinal barrier; BUI, brain uptake index; CNS, central nervous system; E17bG, estradiol 17-b glucuronide; Mrp, multidrug resistance-associated protein; oat, organic anion transporter; oatp, organic anion transporting polypeptides; RPE, retinal pigment epithelium; RUI, retinal uptake index. Uptake Index Method and Microdialysis Study.…”

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confidence: 99%

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

Fujii

Setoguchi

Kawazu

et al. 2015

Drug Metabolism and Disposition

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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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“…Sampling from this area in a rat is further complicated by the small eye size (4-8 mm diameter) and relatively large lens (≥ 4 mm diameter) in the posterior chamber. 17 While one study has employed microdialysis for vitreal fluid collection from rats 18 , most ocular studies involving microdialysis utilize rabbits because of the larger posterior segment. 19 Certain drawbacks of microdialysis are limiting toward the study of vitreal fluids from smaller vertebrates.…”

Section: Introductionmentioning

confidence: 99%

Measurement of Region-Specific Nitrate Levels of the Posterior Chamber of the Rat Eye Using Low-Flow Push−Pull Perfusion

2008

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The determination of the presence of nitric oxide (NO) metabolites in the rat vitreous cavity in a regioselective manner is complicated by the size and shape of the eye as well as the diffusivity of the molecule and its metabolites. In this work, in vivo low-flow push-pull perfusion sampling was utilized with a rapid capillary electrophoretic assay to monitor levels of the major NO metabolite, nitrate, at the vitreoretinal interface (VRI) of normal and aged rat models. The sampling probe tips were placed in three different positions in the posterior chamber through a 29-gauge guide needle. Sampling was performed along the VRI over the optic nerve head and regions peripheral to the optic nerve head. Additionally, samples were collected from the middle vitreous region to compare to VRI sampling. A significant (P<0.05) difference in the perfusate nitrate concentration was observed in each location, which may be due to the source of NO production or the clearance mechanism of the molecule from vitreous cavity. Infusion of L-NAME with physiological saline led to a significant decrease (35%) in the observed nitrate level. LFPPP was then utilized to observe nitrate levels after an average of 4.5 months of aging. A 3-fold increase in the mean level of nitrate over the optic nerve head was observed in mature animals compared to younger control animals. Precise measurement of NO metabolites along the VRI may provide insights into the function of NO in maintaining homeostatic conditions and the molecular changes at the diseased retina.

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Application of microdialysis to evaluate the efflux transport of estradiol 17-β glucuronide across the rat blood–retinal barrier

Cited by 24 publications

References 28 publications

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

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

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

Measurement of Region-Specific Nitrate Levels of the Posterior Chamber of the Rat Eye Using Low-Flow Push−Pull Perfusion

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