Active efflux across the blood-brain barrier: Role of the solute carrier family

Kusuhara, Hiroyuki; Sugiyama, Yuichi

doi:10.1602/neurorx.2.1.73

Cited by 208 publications

(148 citation statements)

References 100 publications

(121 reference statements)

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“…Despite the high affinity of E 2 17βG with MRP1, there is a considerably lower expression level of MRP1 compared to MRP2 in Caco-2 cells. Hence, E 2 17βG could be considered as a relatively specific MRP2 substrate (42,43) in this study. One major advantage of the bi-directional transport study over the accumulation study was the polarization and tight junction formation of these Caco-2 cells, which provided the best possible in vitro simulation of intestinal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Jia

2008

J Pharm Pharm Sci

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-Purpose. Oral drug development had been hindered by the bioavailability issue despite vast market popularity. Lipid excipients had shown to enhance bioavailability of a number of reformulated hydrophobic oral drugs, yet the underlying mechanisms of action by lipids are still unclear. One proposed mechanism is that lipid excipients could facilitate drug uptake by altering the activities of apical membrane intestinal efflux transporters. Thus, this study aimed to investigate the effects of 1-monopalmitin, 1-monoolein and 1-monostearin on the efflux activity and protein expression of multidrug resistance-associated protein 2 (MRP2) in vitro. Methods. The 24-hour non-cytotoxic ranges of these monoglycerides were first determined using MTS and LDH assays in Caco-2 cells. Then, both accumulation and bidirectional transport studies were conducted using 10 μM rhodamine 123 (Rh123) and 10 nM estradiol 17 β-D-glucuronide (E 2 17βG), respectively, to assess the functional activities of MRP2. 50 µM MK-571, a specific MRP1 and MRP2 inhibitor, was used as the positive control in both studies. Western blotting was followed to determine the effect of these monoglycerides on MRP2 protein expression. Results. Caco-2 cells were viable when treated with 1-monopalmitin, 1-monostearin and 1-monoolein at concentrations equal or less than 1000 µM, 1000 µM and 500 µM, respectively. Cells treated with 1-monoplamitin, 1-monostearin, 1-monoolein and MK571 resulted in significant increases in Rh123 accumulation and decreases in E 2 17βG efflux ratio compared to the control (medium treated only). MRP2 protein expressions in 1-monopalmitin and 1-monoolein treated cells were decreased by 19% and 35% compared to the control; however, there was no change of MRP2 protein expression in 1-monostearin treated cells. Conclusions. These findings suggested that 1-monoolein, 1-monostearin and 1-monopalmitin could attenuate the activity of MRP2 and possibly other efflux transporters in Caco-2 cells. The reduction of efflux activity of MRP2 by 1-monoolein treatment could be partially accounted by the non-specific down-regulation of MRP2 protein expression.

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Section: Discussionmentioning

confidence: 99%

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Jia

2008

J Pharm Pharm Sci

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“…Typically, molecules that are capable of crossing the BBB by passive diffusion are small (M r <500 Da), lipophilic and uncharged at physiological pH [12,13] . Various facilitated or energy-dependent transporters and receptors are highly expressed at the BBB; examples of such transporters include members of the organic cation transporter (OCT) families, organic anion transporters (OATs) and multidrug resistance proteins (MRPs) [14,15] . A number of studies aimed at enhancing the distribution of therapeutics in the brain based on carrier-and receptor-mediated transport systems have been performed [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

et al. 2012

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Aim: Dexibuprofen, the S(+)-isomer of ibuprofen, is an effective therapeutic agent for the treatment of neurodegenerative disorders. However, its clinical use is hampered by a limited brain distribution. The aim of this study was to design and synthesize brain-targeting dexibuprofen prodrugs and to evaluate their brain-targeting efficiency using biodistribution and pharmacokinetic analysis. Methods: In vitro stability, biodistribution and pharmacokinetic studies were performed on male Sprague-Dawley rats. The concentrations of dexibuprofen in biosamples, including the plasma, brain, heart, liver, spleen, lung, and kidney, were measured using high pressure lipid chromatography (HPLC). The pharmacokinetic parameters of the drug in the plasma and tissues were calculated using obtained data and statistics. Results: Five dexibuprofen prodrugs that were modified to contain ethanolamine-related structures were designed and synthesized. Their chemical structures were confirmed using 1 H NMR, 13 C NMR, IR, and HRMS. In the biodistribution study, 10 min after intravenous administration of dexibuprofen (11.70 mg/kg) and its prodrugs (the dose of each compound was equivalent to 11.70 mg/kg of dexibuprofen) in male Sprague-Dawley rats, the dexibuprofen concentrations in the brain and plasma were measured. The C brain /C plasma ratios of prodrugs 1, 2, 3, 4, and 5 were 17.0-, 15.7-, 7.88-, 9.31-, and 3.42-fold higher than that of dexibuprofen, respectively (P<0.01). Thus, each of the prodrugs exhibited a significantly enhanced brain distribution when compared with dexibuprofen. In the pharmacokinetic study, prodrug 1 exhibited a brain-targeting index of 11.19 {DTI=(AUC brain /AUC plasma ) 1 /(AUC brain /AUC plasma ) dexibuprofen }. Conclusion:The ethanolamine-related structures may play an important role in transport across the brain blood barrier.

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“…Because of highly developed tight junctions between adjacent cells and a paucity of fenestrae from the diffusion barrier, various transport systems play pivotal roles in both the uptake of water-soluble nutrients and peptides from the circulating blood and the efflux of xenobiotic and endogenous compounds from the brain interstitial space (Kusuhara and Sugiyama, 2005). The active efflux system in the BBB keeps the unbound concentrations of exogenous compounds in the brain interstitial space lower than those in the blood to attenuate their effect in the central nervous system and also inactivates neuroactive compounds produced in the brain by transferring them to the blood.…”

Section: Introductionmentioning

confidence: 99%

“…Characterization of this process using various organic anions as inhibitors has suggested that the efflux of amphipathic and hydrophilic organic anions is mediated by distinct transporters (Kusuhara and Sugiyama, 2005). Furthermore, a mutual inhibition study suggested that the efflux of amphipathic organic anions, such as bile acids and cyclo-D-Trp-D-Asp-Pro-D-ValLeu (BQ-123), is mediated by multiple transporters (Kitazawa et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Miyajima

Kusuhara²,

Fujishima³

et al. 2011

Drug Metabolism and Disposition

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ABSTRACT:The present study investigated the efflux transport systems of organic anions across the blood-brain barrier (BBB) using dehydroepiandrosterone sulfate (DHEAS) as a probe. The elimination of DHEAS from the brain after microinjection into the cerebral cortex was characterized in wild-type mice and mice with deficiency of well characterized organic anion transporters, organic aniontransporting polypeptide 1a4 (Oatp1a4)/Slco1a4 and organic anion transporter 3 (Oat3)/Slc22a8, at the BBB. The saturable efflux of DHEAS from the brain was completely inhibited by probenecid, benzylpenicillin, and estrone-3-sulfate and moderately inhibited by taurocholate and p-aminohippurate (50-57%). Uptake of DHEAS and estrone-3-sulfate was greater in murine Oat3 cRNA-injected oocytes than that in water-injected oocytes. Efflux of these compounds from the brain was significantly delayed in Oat3(؊/؊) mice compared with that in wild-type mice, indicating that indeed Oat3 is functionally important in vivo. Furthermore, probenecid and taurocholate inhibited DHEAS efflux completely in Oat3(؊/؊) mice. Contrary to the past report in rats that suggested involvement of Oatp1a4, specific uptake of DHEAS and estrone-3-sulfate by murine Oatp1a4 was not detected in vitro, and efflux of both compounds from the brain was not altered in Oatp1a4(؊/؊) mice. There was no significant difference in the uptake of DHEAS by brain slices prepared from wild-type, Oatp1a4(؊/؊), and Oat3(؊/؊) mice. Taken together, these results suggest that Oat3 plays a significant role in the efflux of steroid conjugates across the BBB in mice and that the BBB also expresses other unknown organic anion transporters for the efflux of DHEAS. Transport mechanisms of organic anions at the BBB are far more diverse than they were assumed to be.

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Active efflux across the blood-brain barrier: Role of the solute carrier family

Cited by 208 publications

References 100 publications

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

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