title: Effect of the p-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: an in vivo microdialysis study in freely moving rats.
abstract: The p-glycoprotein is a transmembrane efflux transporter found on the luminal side of the capillary endothelial cells that comprise the blood-brain barrier. This study examined the effect of a p-glycoprotein inhibitor, cyclosporin A, on the distribution to the brain of a p-glycoprotein substrate, rhodamine-123, in freely moving rats using intracerebral microdialysis coupled with on-line HPLC analysis. Results from crossover experiments show that the coadministration of cyclosporin A significantly increased the distribution of rhodamine-123 to the brain. The plasma disposition of rhodamine-123 was unchanged by cyclosporin A, indicating that the change in brain exposure was mediated by a process at the level of the blood-brain barrier, possibly by inhibition of the p-glycoprotein efflux transporter. This finding suggests a functional activity of the p-glycoprotein in the blood-brain barrier and validates an in vivo model to examine the role of this transporter in the brain distribution of drugs.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: D W
authors.initials: DW
authors.lastname: Miller
authors.forename: W F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D016572:Cyclosporine / Q000494:pharmacology*; D008124:Locomotion; D008297:Male; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D012235:Rhodamines; D020112:Rhodamine 123; D016572:Cyclosporine