SLC Transporters

Figure 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

Seithel A, Karlsson J, Hilgendorf C, Bjorquist A, Ungell AL (2006) Variability in mRNA expression of ABC- and SLC-transporters in human intestinal cells Comparison between human segments and Caco-2 cells. Eur J Pharm Sci 28 291-9. 

Keywords Drug transporter SLC-transporter ABC transporter Drug delivery Intestinal absorption barrierl... 

Englund, G., Rorsman, F., Roennblom, A., Karlbom, U., Lazorova, L., Grasjoe, J., Kindmark, A. and Artursson, P. (2006) Regional levels of drug transporters along the human intestinal tract co-expres sion of ABC and SLC transporters and comparison with Caco-2 cells. European Journal of Pharmaceutical Sciences, 29, 269-277. 

The barrier to paracellular diffusion potentially isolates the brain from many essential polar nutrients such as glucose and amino acids that are required for metabolism and, therefore, the BBB endothelium must contain a number of specific solute carriers (transporters) to supply the CNS with its requirements for these substances. The formation of tight junctions essentially confers on the BBB the properties of a continuous cell membrane, both in terms of the diffusional characteristics imposed by the lipid bilayer, and the directionality and properties of the specific transport proteins, and solute carriers (SLC) that are present in the cell membrane. Examples of BBB solute carriers (SLC transporters) are listed in Table 27.2. 

Transporter (SLC) Transporter Subtype Gene Name BBB Location Orientation3 Substrates/Mechanism... 

II.I.2.1 Drug Transport Mediated by SLC Transporters Using Eukaryotic Cells 532... 

Carl SM, Lindley DJ, Couraud PO, Weksler BB, Romero I, Mowery SA et al (2010) ABC and SLC transporter expression and Pot substrate characterization across the human CMEC/D3 blood-brain barrier cell line. Mol Pharm 7 1057-1068... 

FIGURE 34.2 ABC transporters (green) that transport the substrate (S) in one defined direction are called primary transporters because no other additional biochemical step than the ATP hydrolysis or GSH co-transport is needed for (S) transport. SLC transporters (3, pink) need the activation by one or two ion transporters before S transport occurs. In this model, 1, is the Na+, K+-ATPase and 2, the Na, H antiporter providing the H driving force for S transport... 

The location of transporters at the cell plasma membrane is a critical issue because most of the cells involved in the A, D, E pharmacokinetic processes are polarized. Hence then-apical (luminal) and basolateral (abluminal) membranes do not have the same populations of transporters (Eigure 34.4). The same transporter is rarely found at both the apical and basolateral membranes. But most of the ABC and SLC transporters are located at either the apical or the basolateral epithelial membranes, and their location helps to define the direction of substrate transport and the resulting pharmacokinetic event. 

FIGURE 34.4 A schematic proposal for cellular and subcellular distribution of ABC (green) and SLC (pink) transporters on the apical and basolateral membranes of an epithelial cell. SLC import and ABC export at the apical membrane of the unchanged xenobiotic (X), and ABC export of glucuronated-X (X-OG) at the basolateral membrane subcellular events include mitochondrial uptake of X by a SLC transporter and X-OG efflux from the lumen of the ER where cytochrome P450 (CYP) and UDP-glu-curonosyltransferase (UGT) produce X-OH and X-OG metabolites. 

FIGURE 34.6 Distribution of the main drag ABC (green) and SLC (pink) transporters on the basolateral (sinusoid) and apical (bile canaliculus) membranes of the human hepatocytes. SLC transporters at the basolateral membrane mainly define active hepatic uptake whereas ABC transporters at the basolateral and bile canaliculus membranes efflux drugs and their metabolites in blood or bile, respectively. 

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