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

J Pharm Sci. 2006 Sep;95(9):1944-53. doi: 10.1002/jps.20658.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Acridines / pharmacokinetics
  • Animals
  • Animals, Genetically Modified
  • Blood-Brain Barrier / physiology*
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Genes, MDR / genetics
  • Guinea Pigs
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity
  • Tetrahydroisoquinolines / pharmacokinetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridines
  • Tetrahydroisoquinolines
  • Elacridar