RGD Reference Report - Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier. - Rat Genome Database

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Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier.

Authors: Cutler, L  Howes, C  Deeks, NJ  Buck, TL  Jeffrey, P 
Citation: Cutler L, etal., J Pharm Sci. 2006 Sep;95(9):1944-53.
RGD ID: 1598561
Pubmed: PMID:16850390   (View Abstract at PubMed)
DOI: DOI:10.1002/jps.20658   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
establishment of endothelial blood-brain barrier  IMP 1598561 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)


Additional Information