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

Abstract

The brain uptake of xenobiotics is restricted by the blood-brain brain barrier formed by brain capillary endothelial cells. Active efflux transport systems in the blood-brain barrier work as a detoxification system in the brain by facilitating removal of xenobiotic compounds from the brain. Drugs, acting in the brain, have to overcome such efflux mechanisms to achieve clinically significant concentration in the brain. Multiple transporters are involved in this efflux transport in the brain capillaries. In the past few years, considerable progress has been made in the cloning of these transporters and their functional characterization after heterologous expression. Members of the solute carrier family (SLC) play an important role in the efflux transport, especially for organic anions, which include organic anion transporting polypeptides (OATP/SLCO) and organic anion transporters (OAT/SLC22A). It is believed that coordination of the members of SLC family, and ABC transporters, such as P-glycoprotein, multidrug resistance protein, and breast cancer-resistant protein (BCRP/ABCG2), allows an efficient vectorial transport across the endothelial cells to remove xenobiotics from the brain. In this review, we shall summarize our current knowledge about their localization, molecular and functional characteristics, and substrate and inhibitor specificity.

FIG. 1.

Schematic diagram of the efflux transport mechanisms at the blood-brain barrier. In vivo experiments employing BEI method has suggested that the efflux mechanism for hydrophilic organic anions is accounted for by Oat3, and that for amphipathic organic anions is accounted for partly by Oatp1a4 (taurocholate- and digoxin-inhibitable pathway) and partly by unknown transporter. The unknown transporter is involved in the efflux of E3S, E217βG, and BQ-123. On the luminal membrane, Oatp1a4 and Oatp1c1 are involved in the uptake of amphipathic organic anions and peptide, and thyroxine (T4). E3S = estrone-3-sulfate; E217βG = estradiol 17β glucuronide.

FIG. 2.

Effect of probenecid, taurocholate, digoxin, and p-aminohippurate on the elimination of E217βG after intracerebral microinjection. E217βG is eliminated from the brain at a rate constant of 0.037 ± 0.001 min⁻¹. Probenecid (A), taurocholate (B), p-aminohippurate (C), and digoxin (D) were simultaneously microinjected into the cerebrum, and their effect on the elimination of E217βG from the cerebrum was examined. Each value of expected concentration is estimated by the concentration in the injectate divided by the dilution factor. Results are given as a ratio with respect to the elimination rate constant determined in the absence of unlabeled inhibitors. Each points represent mean ± SEM (n = 3). *, Significant different from the control (p < 0.05). Reproduced with permission from Sugiyama et al. Characterization of the efflux transport of 17β-estradiol-D-17β-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther 298:316–322. Copyright© The American Society for Pharmacology and Experimental Therapeutics, 2001. All rights reserved.

FIG. 3.

Limitation of Oatp1a4-mediated uptake of [d-penicillamine-2,5]-enkephalin by P-gp at the BBB. A: The initial uptake clearance of [d-penicillamine-2,5]-enkephalin in the right cerebral hemisphere was determined in wild-type and Mdr1a P-gp knockout mice after 180 s of perfusion. Data are presented as mean ± SD (n = 4). ***, p < 0.001. B: The effect of inhibitors was examined for the brain uptake of [d-penicillamine-2,5]-enkephalin in Mdr1a P-gp knockout mice after 120 s of perfusion. The concentration used in this experiment is as follows: E217βG, 200 μm; fexofenadine, 150 μm; dexverapamil, 300 μm; digoxin 25 μm. Data are presented as mean ± SD (n = 4). ***, p < 0.001; **, p < 0.01; and *, p < 0.05. Reproduced with permission from Dagenais et al. Uptake and efflux of the peptidic δ-opioid receptor agonist. Neurosci Lett 301:155-158. Copyright © 2001, Elsevier. All rights reserved.

FIG. 4.

Vectorial transport of benzylpenicillin in the double transfectant of rat Oat3 and mouse RST in LLC-PK1. Transcellular transport of benzylpenicillin (0.5 μm) across LLC-PK1 monolayers expressing rOat3 and both rOat3 and mRST (rOat3/mRST: double transfectant) was compared with that across the control LLC-PK1 monolayer. Open and closed circles represent the transcellular transport in the apical-to-basal and basal-to-apical directions, respectively. Each point represents the mean ± SEM (n = 3). Reproduced with permission from Imaoka et al. The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules. J Am Soc Nephrol 15:2012-2022. Copyright © 2004, Lippincott Williams & Wilkins. All rights reserved.