title: Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier.
abstract: The objective of this study was to establish the optimal blood concentrations of the potent P-glycoprotein (P-gp) inhibitor GF120918 (Elacridar) required to achieve maximal knockout of this efflux transporter in the blood-brain barrier (BBB) of mice, rats, and guinea pigs. Genetic mdr1a/b(-/-) knockout mice and "chemical" P-gp knockout mice, rats, and guinea pigs, generated by 24 h continuous infusion of GF120918, were used to investigate the effects of P-gp modulation on the brain penetration of SB-487946. Genetic mdr1a/b(-/-) knockout mice demonstrated a >70-fold increase in brain:blood ratio of SB-487946 compared to mdr1a/b(+/+) wild-type mice. There was a similar increase in SB-487946 brain:blood ratio in GF120918-treated mice (ca. >67-fold) and rats (ca. 95-fold) but a significantly smaller increase (ca. 10-fold) in guinea pigs treated with GF120918. An appreciable difference was found in the BBB functional effect of P-gp efflux in rodents. GF120918 blood EC90 in mice and rats were similar however, the EC90 in guinea pigs was ca. 10-fold higher, suggesting a species difference in the activity of P-gp at the BBB in some rodents. This study establishes the optimal blood concentrations of GF120918 in relation to SB-487946, to achieve chemically induced P-gp knockout in rodents.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. Leanne.Cutler@gsk.com
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: Colin
authors.initials: C
authors.lastname: Howes
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Deeks
authors.forename: Tania L
authors.initials: TL
authors.lastname: Buck
authors.forename: Phil
authors.initials: P
authors.lastname: Jeffrey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000166:Acridines / Q000493:pharmacokinetics; D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D019450:Genes, MDR / Q000235:genetics; D006168:Guinea Pigs; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; C083501:Elacridar