Roles of Inner Blood-Retinal Barrier Organic Anion Transporter 3 in the Vitreous/Retina-to-Blood Efflux Transport of <i>p</i>-Aminohippuric Acid, Benzylpenicillin, and 6-Mercaptopurine

Hosoya, Ken; Makihara, Akihide; Tsujikawa, Yuki; Yoneyama, Daisuke; Mori, Shinobu; Terasaki, Tetsuya; Akanuma, Shin Ichi; Tomi, Masatoshi; Tachikawa, Masanori

doi:10.1124/jpet.108.146381

Cited by 63 publications

(40 citation statements)

References 24 publications

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“…It is jpet.aspetjournals.org well known that ocular pharmacokinetic studies are animal intensive requiring sacrifice of approximately 36 animals (four animals per time point and nine time points) to obtain time course data for each compound. Although microdialysis experiments are well established for vitreous humor drug levels (Majumdar et al, 2006;Hosoya et al, 2009), currently there are no reliable methods available to quantify drug levels in other ocular tissues in a continuous manner. Furthermore, trans-scleral drug delivery is not well understood in terms of influence of drug properties on target tissue delivery.…”

Section: ␤-Blockermentioning

confidence: 99%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight ␤-blockers. The Kt:b was in the order intact tissue, dry weight method Ն intact tissue, wet weight method corrected for tissue water and drug in tissue water Ͼ Ͼ intact tissue, wet weight method Ͼ homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) Ͼ trabecular meshwork Ͼ retina Ͼ sclera ϳ optic nerve; propranolol Ͼ betaxolol Ͼ pindolol ϳ timolol ϳ metoprolol Ͼ sotalol ϳ atenolol ϳ nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R 2 of 0.7-0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R 2 of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all ␤-blockers and for some lipophilic ␤-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R 2 of 0.985-0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater transscleral delivery to the retina and vitreous.

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Section: ␤-Blockermentioning

confidence: 99%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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“…[2][3][4] Efflux transport systems provide further barriers for the retina, by actively removing cytotoxic drugs and specific xenobiotic compounds from the retina and transferring them back into the systemic circulation. 5,6 P-glycoprotein (P-gp), a 170-kDa protein encoded by the multiple drug resistance human MDR1 gene, is a member of the ABC superfamily of energy-dependent transport systems. 7 As a well-characterized efflux transporter, P-gp is strongly expressed by retinal vascular endothelial cells 8 and has recently been identified in human RPE.…”

mentioning

confidence: 99%

Expression and Activity of p-Glycoprotein Elevated by Dexamethasone in Cultured Retinal Pigment Epithelium Involve Glucocorticoid Receptor and Pregnane X Receptor

Zhang

Lü

Sun

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate whether dexamethasone has an effect on functional expression of p-glycoprotein in cultured human RPE and, if so, whether this occurs through interaction with glucocorticoid receptor (GR) and pregnane X receptor (PXR).METHODS. The human RPE D407 was treated with increasing concentrations of dexamethasone and/or RU486 for various time periods up to 24 hours. Treated cells were collected for cell viability, expressions of p-glycoprotein and PXR, and rhodamine 123 accumulation assays. GR expression plasmid and rifampicin were chosen to investigate the relationship of GR/PXR activation and p-glycoprotein expression.RESULTS. Significant increases in p-glycoprotein, as indicated by mRNA and protein levels, as well as by functional activity, were induced within 12 hours of dexamethasone treatment, persisted as long as 24 hours, and were dose-dependent and attenuable with coculture of RU486. In parallel, a dosedependent upregulation of PXR was notable at both mRNA and protein levels by 24 hours of dexamethasone treatment, and was partially reversible with RU486 coculture. Additionally, transfection of GR expression plasmid increased the transitional expressions of PXR and p-glycoprotein in untreated cells, and enhanced PXR transcriptional expression in dexamethasone-treated cells. Further, PXR silencing inhibited the dexamethasone-induced p-glycoprotein alterations; however, rifampicin had no apparent effects on the dexamethasoneinduced p-glycoprotein alterations. CONCLUSIONS.Our results suggest for the first time that expression and activation of p-glycoprotein involve GR and PXR in human RPE. (Invest Ophthalmol Vis Sci. 2012;53:3508-3515) DOI:10.1167/iovs.11-9337 R PE plays an essential role in protecting neural tissues from toxic materials and in maintaining vision and neural function in the retina by forming the outer blood-retinal barrier (BRB). It has been demonstrated that the outer BRB not only regulates the ionic environment of the subretinal space, secretes factors for structural integrity of the retina, phagocytizes shed outer segments of photoreceptors, and participates in the visual cycle, 1 but also limits vitreal penetration of drugs administered by the systemic and transscleral routes. 2-4 Efflux transport systems provide further barriers for the retina, by actively removing cytotoxic drugs and specific xenobiotic compounds from the retina and transferring them back into the systemic circulation.5,6 P-glycoprotein (P-gp), a 170-kDa protein encoded by the multiple drug resistance human MDR1 gene, is a member of the ABC superfamily of energy-dependent transport systems.7 As a well-characterized efflux transporter, P-gp is strongly expressed by retinal vascular endothelial cells 8 and has recently been identified in human RPE. 9 P-gp displays broad specificity, accepting many structurally, functionally, and mechanistically unrelated compounds, 10 and its role in limiting drug penetration across biological barriers is well established. Although efflux pumps such as P-gp are best known ...

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“…luminal and abluminal [198], retinal pigmented epithelial cells, basolateral [198] rOATP2B1 retina [195] rOATP3A1 retina [195] rOATP4A1 retina [195,201] retina [201] human OCT1 retinal pigmented epithelium [202] OCT2 retina [194] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 44 OCT3 retina [194] OCTN2 retina [194] rat rOCT1 retina [195]{ rOCT2 retina [195]{ mouse mOCT3 retinal pigmented epithelial cells [203] mOCTN1 blood retinal capillary epithelial cells [204] mOCTN2 blood retinal capillary epithelial cells [204] rat rOAT2 retina [195] rOAT3 retina [195], Blood retinal capillaries [205] primary cultured blood retinal capillary endothelial cells [205] blood retinal capillary endothelial cells: abluminal …”

Section: Drug Metabmentioning

confidence: 99%

Drug Transporters in the Central Nervous System

Stieger

Gao

2015

Clin Pharmacokinet

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Drug targets in the central nervous system (CNS) are numerous and important for drug therapy, e.g., of epilepsy or pain. Drugs and other xenobiotics as well as nutrients cannot freely cross the blood-brain barrier or freely enter cells across plasma membranes and therefore require transport systems. This overview summarizes the current knowledge on the expression of drug transporters in barriers shielding the CNS from the systemic circulation and as such controlling the pharmacokinetics of drugs in the CNS. The main drug transporter families covered are SLCO, SCL22A, ABCB, and ABCC, as genes of these families code for numerous drug transporters. While knowledge on messenger RNA expression in humans, rats, and mice is remarkable, there is clearly a gap in knowledge on the subcellular expression of transporters in specific cells in the CNS and in the barriers shielding the CNS from the systemic circulation. Recent methodologic developments including synthesis of drugs and endogenous substances for imaging will in the future allow the investigation of the function and physiologic role of transporters in the CNS including difficult-to-access systems such as the choroid plexus. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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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

Cited by 63 publications

References 24 publications

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Expression and Activity of p-Glycoprotein Elevated by Dexamethasone in Cultured Retinal Pigment Epithelium Involve Glucocorticoid Receptor and Pregnane X Receptor

Drug Transporters in the Central Nervous System

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