ReviewEfflux transport systems for organic anions and cations at the blood–CSF barrier
Introduction
The choroid plexus (CP) is a leaf-like, highly vascularized organ that protrudes into the ventricles. It secretes the cerebrospinal fluid (CSF) which fills the ventricular system and the subarachnoideal space, and circulates around the brain and spinal cord before it is reabsorbed into the blood circulation primarily by the arachnoid villi [1], [2]. The CSF maintains the working environment of the brain by providing buoyancy to protect the brain and by acting as a buffer reservoir or as a source of necessary osmolytes. The CP consists of fenestrated capillaries surrounded by a tight monolayer of epithelial cells. The choroid plexus epithelial cells (CPE) are polarized to form brush border (BBM) and basolateral (BLM) membranes facing towards the CSF and plasma, respectively. Due to fenestrated capillaries in the CP, compounds in the blood have free access to the BLM of the CPE; however, tightly sealed cell junctions between the epithelial cells prevent free exchange of compounds between the blood and CSF, and provide a barrier function between the CSF and the blood circulation (blood–CSF barrier). In addition, the CPE has detoxification systems, including metabolic enzymes and efflux transport systems, to facilitate the elimination of xenobiotics and endogenous wastes from the CSF to the circulating blood. This, together with the blood–brain brain barrier formed by brain capillary endothelial cells, prevents their accumulation in the central nervous system [3], [4], [5], [6], [7], [8]. Drugs acting in the central nervous system have to overcome these barriers to achieve clinically significant concentrations in the central nervous system.
The efflux transport of organic compounds across the cell monolayer is characterized by vectorial transport, which plays a major role in the hepatobiliary transport and urinary secretion of organic anions and hydrophilic organic cations. Recently, a number of transporters have been cloned and their functional characterization has been carried out [6], [9], [10], [11], [12], [13], [14], [15]. This has allowed the elucidation of the molecular characteristics of the efflux transport systems expressed at the CP as summarized in Table 1. The primary purpose of the present manuscript is to illustrate the efflux transport systems for organic anions and cations in the CP.
Section snippets
Pharmacokinetic quantification of efflux transport from the CSF
A sequential determination of the CSF concentration after intracerebroventricular (i.c.v.) administration (CCSF) allows us to determine the elimination rate constant (ke) as described by the following differential equation,where CLCSF represents the elimination clearance from the CSF. The time profile of the drug concentration in the CSF is affected not only by the elimination clearance, but also by the distribution volume in the ventricles (Vd,CSF). The CLCSF
Molecular characteristics of drug transporters
In this section, the molecular characteristics of the uptake transporters, such as Oatp/OATP, Oat/OAT, Oct/OCT and PEPT are described, as well as the ABC transporters, such as Mrp/MRP and P-glycoprotein. The prefixes m, r and h represent different species, i.e. mice, rats and humans, in the following text.
Efflux transport mechanisms for organic anions in the choroid plexus
The uptake mechanisms for organic anions at the brush border surface of the CP can be subdivided into two groups in terms of substrate specificity: One for amphipathic organic anions, such as taurocholate, E217βG and estrone sulfate, and the other for hydrophilic and small organic anions, such as PAH and benzylpenicillin (Fig. 1). These two systems have similar characteristics to the hepatobiliary and urinary transport systems for organic anions, respectively, and are primarily accounted for by
Efflux transport mechanism for organic cations in the choroid plexus
Miller and Ross [144] measured the extraction of NMN in vivo using the ventriculocisternal perfusion technique. The extraction of NMN during perfusion from the lateral ventricles to the cisternal magna was greater than that of inulin and was reduced by the addition of mepiperhenidol to the perfusate, suggesting involvement of an organic cation transporter in the extraction [144]. Other organic cations, such as cimetidine, choline, and TEA, typical substrates of renal organic cation
Discussion and future aspects
The present review summarizes the current status of the efflux transport mechanisms for organic ions in the CP. The many published studies have provided molecular insights into the uptake systems operating at the BBM of the CP. Due to limitations in methodology, the excretion process for organic ions has not been fully characterized yet and the molecular characteristics of the transporters involved in this process remain unknown. ABC transporters, such as MRPs and/or alternatively membrane
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