Choroid plexus controls brain availability of anti-HIV nucleoside analogs via pharmacologically inhibitable organic anion transporters.
OBJECTIVE
In AIDS, 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 brain impairment in late stages of the infection. 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 nucleoside 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 zidovudine was the highest, although moderate, followed by that of stavudine. The permeability coefficients of the other drugs tested were low. Zidovudine influx into the CSF is independent of thymidine 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 benzbromarone.


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 nucleoside analogs to the brain.
Strazielle
Nathalie
N
Research and Development in Neuropharmacology, INSERM U433, Faculté de Médecine Laennec, Rue Guillaume Paradin, 69372 Lyon cedex 08, France. strazielle@lyon.inserm.fr
Belin
Marie-Françoise
MF
Ghersi-Egea
Jean-François
JF
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001682:Biological Availability; D001812:Blood-Brain Barrier; D002831:Choroid Plexus / Q000166:cytology / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects; D012367:RNA, Viral / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000493:pharmacokinetics / Q000627:therapeutic use; D019562:Viral Load; D015215:Zidovudine / Q000493:pharmacokinetics / Q000627:therapeutic use
D019380:Anti-HIV Agents; D012367:RNA, Viral; D015215:Zidovudine; D013936:Thymidine