Investigation of the efflux transport mechanism across the blood-brain and blood-cerebrospinal fluid barriers, and establishment of a method for predicting disposition of a drug in the central nervous system

Investigation of the efflux transport mechanism across the blood-brain and blood-cerebrospinal fluid barriers, and establishment of a method for predicting disposition of a drug in the central nervous system

It is necessary to have information about the permeability of a drug across the key barriers, i.e. the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) in order to predict its disposition in the central nervous system. An experimental system using isolated choroid plexus was established for that purpose. Using this technique, it was found that many drugs are actively eliminated from the cerebrospinal fluid through the BCSFB into the blood, and the driving force for this has been identified. At present, the development of a method for predicting the intracerebral distribution in vivo has been carried out using a series of drugs as model compounds including an anti-AIDS agent, a number of quinolone antibiotics and antidementia agents. Such analyses, have recently allowed us to collect a great deal of interesting data. Although the BBB has been regarded as a "static wall" consisting of anatomical features such as the tight junction which connects endothelial cells to each other, recent advances in kinetic and molecular biological research have changed the way we look at this dynamic barrier. It is now known that efflux transporters, such as P-glycoprotein, also provide a barrier function by transporting xenobiotics including drugs from inside the brain capillary endothelial cells to the blood resulting in an apparently low BBB permeabilitiy. It is suggested that transporters other than P-glycoprotein also play a role in the detoxification of xenobiotics in the BBB based on our recent studies using the brain efflux index method. This method enables us to measure efflux transport across the BBB in vivo, using membrane vesicles and a number of molecular biological approaches.