Development of a rational strategy for drug delivery
to the liver, kidney and central nervous system

Transporters can be applied to obtain tissue-selective drug delivery. Figure 6 illustrates the transporters which are involved in the uptake and efflux of drugs in the liver, kidney, intestine and the barriers of the central nervous system formed by the brain capillaries and choroid plexus (BBB and BCSFB, respectively). For example, since various transporters are expressed in the blood brain barrier (Fig. 7), drugs designed to be recognized as substrates of uptake transporters, or not to be recognized by efflux transporters, may reach high concentrations in the brain and exert a more potent therapeutic effect. Transporters in the liver or kidney are important for determining the elimination pathway of drugs. In the case of drugs that target the liver, transporters responsible for their uptake will play an important role in their pharmacological effect in the liver. In the case of drugs which are given to patients suffering from renal dysfunction, the plasma concentrations of drugs eliminated predominantly by the kidney will exhibit large interindividual differences depending on the degree of dysfunction. Thus, drugs, which have the same therapeutic effect, but are eliminated by the liver, will be preferred for treatment. In the case of certain antineoplastic drugs, it has been suggested that biliary excretion is associated with their side effects and, in this case, blocking the biliary excretion will reduce the incidence of side effects. Drug design, aimed at controlling the recognition by such transporters, is now being investigated.
As for biologically active peptides, genes, anti-sense oligonucleotides, ribozymes, RNAi(s), etc., they have been investigated to optimize their clinical applications as drugs. However, generally, their membrane permeability is low due to their large molecular weight and low lipophilicity. This prevents their direct clinical application. In order to deliver these materials to a target organ, it is necessary to develop a carrier which shows tissue-selective distribution, or finally, to remodel/redesign the structure of such materials. The receptors for biologically active peptides are promising targets since they exhibit tissue-selective expression and internalization of receptor-ligand complexes occurs quickly. Receptors that are highly expressed have been identified in the blood brain barrier or in cancer cells. It is now actually possible to deliver drugs to the brain or tumorsby making a complex with the carrier designed for the receptors, including specific ligands and monoclonal antibodies.
Other research topics include establishing a strategy for drug-design in order to deliver drugs to the target organ specifically based on differences in the substrate specificity of transporters.

Fig. 6

Fig. 7