Blood-brain interfaces: relevance to cerebral drug metabolism
Résumé
The brain, with the exception of the circumventricular organs (CVOs), is partially protected from the invasion of blood-borne chemicals by the tight junctions that link adjacent cerebral endothelial cells and form the structural basis of the blood-brain barrier (BBB). In addition to the BBB, the epithelial layer of the choroid plexuses and the barrier layer of the arachnoid membrane complex comprise a second system for protecting the brain, a system often referred to as the blood-cerebrospinal fluid (CSF) barrier. In the past several years, several enzymes that are involved in hepatic drug metabolism have been found in the small microvessels from brain, the choroid plexuses, and the leptomeninges (pia plus arachnoid mater) as well as in some CVOs. These drug-metabolizing systems are inducible and may act at these various interfaces as ‘enzymatic barriers' to influx. In particular, the activities of these enzymes in choroidal tissue are so high that the choroid plexuses can well be the major site of drug metabolism in the brain. The fate of intracerebrally formed polar metabolites and the potential of the blood-brain and blood-CSF barriers as sites for metabolic activation-induced neurotoxicity are discussed.