Restriction of drug distribution into the brain by the blood-brain barrier (BBB) is one of the serious issues for DDS. Recent progress in the BBB research has revealed that various transport systems function at the BBB, such as blood-to-brain influx transport and brain-to-blood efflux transport. The blood-to-brain influx transport system facilitates drug permeability across the BBB, such as System L transport for levodopa, while the brain-to-blood efflux transport prevents entry of drug into the brain. Therefore, the way of recognition by BBB transport systems makes important contribution to drug distribution into the brain. Furthermore, using the receptor-mediated transport system at the BBB, non-viral carrier for the DDS to the brain has been reported. This non-viral carrier has succeeded to deliver plasmid DNA and siRNA into the brain. In vitro BBB model is an important technology for estimating BBB permeability of drugs. We have established conditionally immortalized brain capillary endothelial cells from transgenic rats and mice. The BBB permeability of compounds estimated from the uptake study using these cell lines had good correlation to the BBB permeability reported in vivo. The progress in the BBB research provided us important knowledge to understand drug distribution and delivery into the brain.

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A comprehensive and precise list of drug transporters has become available. Moreover, cDNA clones can be obtained easily through researchers, public resources or commercial providers. To date, substrate preferences and other functional characteristics of transporters can be studied by using in vitro expression systems. All information should be accumulated, integrated and utilized. Efficient organ-specific drug delivery should be feasible by appropriately modifying the chemical structure of drugs.
This review article was aimed to introduce recent success in delivery of drugs to target organs via transporters, and to discuss issues that should be considered to establish organ-specific drug delivery system.

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Recently, it has been recognized that the intestinal transporters are the important factor for determining oral drug bioavailability. The efflux transporters in the intestine may limit drug absorption into the enterocyte thereby lowering the amount of drug available to enter the bloodstream. The oral administration of competing low molecular weight compounds, such as verapamil or cyclosporin can enhance the oral bioavailability of efflux transporter substrate drugs. Such competing compounds, however, have themselves pharmacological activity. So the challenge to find inhibitors of the efflux transporters that do not have such drawbacks is necessary.
It has been reported that excipients, which are commonly added to pharmaceutical formulations, may disrupt the function of intestinal efflux transporters and thus enhance the intestinal permeability of a substrate drug. Because inhibition of efflux transporters can have an effect on drug bioavailability, identification of these excipients and their extent of inhibition are therefore important for pharmaceutical development. In addition, understanding the detailed inhibition mechanism of the efflux transport system will contribute to the development of the optimized formulations that give higher oral bioavailability. This review focus on the possibility to improve oral bioavailability by inhibiting the function of efflux transporters, and their inhibition mechanism will be discussed.

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This review summarizes studies on drug delivery system (DDS) utilizing sugar transporter. It has been reported intestinal absorption of various monosaccharide conjugates (glycosides) via Na⁺/glucose cotransporter (SGLT1). Transportability and recognizability of the glycosides by SGLT1 depend on types of sugar, glycoside linkage and aglycone. Therefore, glycosides should be classified by TRN classification for DDS development. Transportability of β-glucoside is the highest among glycosides. Monosaccharide conjugates such as β-glucoside should work as a prodrug, which can be transported by SGLT1. Moreover, disaccharide conjugates have potential as a pre-prodrug.
On the other hand, it has not been reported clear evidence for sugar transporter-mediated delivery of glycosides to brain and kidney.

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In addition to nutrients, influx transporters expressed on the apical membrane of intestinal epithelial cells accept various drugs as substrates. For example, peptide transporter 1 (PEPT1) has been found to be one of the most versatile influx transporters with great substrate range. This observation has been exploited successfully as a mechanism for improving oral bioavailability of drugs such as cefixime and aciclovir. Additionally, the sodium-dependent glucose transporter (SGLT) and the apical sodium-dependent bile acid transporter (ASBT) are currently molecular targets for discovery of anti-diabetic and hypolipidemic drugs, respectively.
This paper will review research on the intestinal influx transporters with special emphasis on their potential application in drug development.

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Drug efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed not only in resistant tumor cells, but also in many normal tissues, including the epithelial apical membrane of the intestine. Thus, efflux transporters may play an important role in the barrier function of the intestine against xenobiotic drugs. On the other hand, several researchers have suggested that the influence of P-gp on intestinal absorption of drugs is relatively limited, since the absorption rates of various P-gp substrates after oral administration are quite high in humans. The controversy remains to be resolved.
Here, we review the effects of intestinal efflux transporters on drug absorption, and discuss the evaluation and prevention of such effects.

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