Development of the drug delivery system for brain and cancer using the inhibitory effect of some drugs on the active efflux : Application of physiological pharmacokinetics.

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[1] Transport mechanism of peptides : Using a monoclonal antibody to transferrin as a model polypeptide, the transport mechanism for piptide in blood-brain barrier (BBB) was examined. The permeability of this antibody for blood-brain barrier was evaluated with in situ brain perfusion system, in vitro isolated and cultured bovine brain endotherial cells. As a result, the existence of receptor-mediated endocytosis pathway was suggested to be existed. By complex formation of this antibody and the polypeptide, it may possibly be improved that the net transfer of the polypeptide into the brain across the BBB.[2] Transport mechanism for hydrophilic drugs : Using quinolone derivatives (NQs) and anti-AIDS drugs (azidothymidine and dideoxyinosine) as model drugs, the mechanism for the disposition in the central nervous system (CNS) were examined with in vivo and in vitro experimental systems. For anti-AIDS drugs, the uptake from blood to brain was suggested to be active transport. In vitro uptake studies using isolated choroid plexus revealed that NQs was pumped out from cerebrospinal fluid to the circulating blood by an active organic anion transport system which is identical with that for benzylpenicillin. In addition, not only anti-AIDS drugs but NQs are also taken up by choroid plexus in a active transport manner.[3] Prediction of the disposition with physiological pharmacokinetics : Analysis based on the distributed model in which the ligand exchange between the plasma, brain, and cerebrospinal fluid is considered revealed that the CNS to plasma unbound concentration ratio of NQs can be predicted using the determined clearance values, which were determined with several experimental systems described above, for the transport across the barriers.