Choroid plexus controls brain availability of anti-HIV XXXX analogs via pharmacologically inhibitable organic anion transporters.

@entity2353 @entity9611 @entity14027 @entity75 @entity281 @entity1014 @entity791 @entity11368
OBJECTIVE: In @entity791 , early suppression of the viral load in the central nervous system is critical for the efficacy of antiretroviral therapy, in order to prevent the emergence of a reservoir of resistant strains of virus, and @entity75 in late stages of the @entity281 . The blood-cerebrospinal fluid (CSF) interface (i.e. the choroidal epithelium) constitutes the most direct route to reach the ventricular meningeal and perivascular infected macrophages, and may modulate the cerebral biodisposition of antiretroviral drugs through various transport systems. Our aim was to address @entity2353 drug transfer specifically across the blood-CSF interface, and identify the possible mechanisms involved in their transport. METHODS: Drug influx and efflux were measured using an in vitro cellular model that reproduces the barrier and transport properties of the blood-CSF interface in vivo. Transport mechanisms were investigated by competition studies. RESULTS: The CSF influx rate of @entity9611 was the highest, although moderate, followed by that of @entity14027 . The permeability coefficients of the other drugs tested were low. @entity9611 influx into the CSF is independent of @entity1014 transport systems, and more importantly is limited by an efflux mechanism. This efflux involves an apical (CSF-facing) carrier belonging to the solute carrier (Slc) 22 family of organic anion transporters, and can be inhibited by a therapeutic concentration of @entity11368 . CONCLUSIONS: The demonstration and characterization of this efflux mechanism is the basis for the development of specific inhibitory agents in view to increase the delivery of antiretroviral @entity2353 analogs to the brain.
