title: P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists.
abstract: CP-122721 and CP-141938 are potent and selective neurokinin-1 (NK(1)) receptor antagonists with very different brain disposition and potency in models of centrally mediated activity. These investigations sought to determine whether differences in potency were related to differences in P-glycoprotein (P-gp) transport at the blood-brain barrier. Both compounds stimulated ATPase activity of human recombinant MDR1 with similar kinetic parameters. Cell-associated drug concentrations of CP-141938 were 9.4-fold lower in KBV1 cells expressing P-gp compared with KB3.1 control cells. In Madin-Darby canine kidney (MDCK) cells expressing human MDR1, asymmetric transport of CP-141938 was 5-fold higher than in wild-type MDCK cells, whereas no asymmetry was observed with CP-122721. In agreement with these differences in cellular transport, the differences in brain/plasma ratio between mdr1a/b(-/-) and FVB mice 1 h following a 3 mg/kg s.c. dose were 3- and 50-fold for CP-122721 and CP-141938, respectively. The effect of inhibiting P-gp efflux on the effects of these agents was evaluated using GR73632-induced foot tapping in gerbils as a model to measure centrally mediated NK(1) antagonism. When gerbils were pretreated with the P-gp inhibitor MS-073 (50 mg/kg s.c.), there was no effect on the activity of CP-122721 (0.05 mg/kg), whereas the percent reversal for CP-141938 (10 mg/kg) increased from 60 to 100%. In gerbils, the brain/plasma ratio for CP-122721 was unaffected by MS-073 pretreatment, whereas the brain/plasma ratio for CP-141938 brain concentrations increased 13-fold. This suggested that P-gp efflux influences the brain disposition and pharmacologic activity of CP-141938, but not CP-122721. Complete response curves for CP-141938 were then determined with respect to dose, and drug concentration in the plasma and brain in the presence and absence of MS-073 pretreatment. The dose and plasma concentration-response curves of CP-141938 were shifted to the left in the presence of MS-073, yet brain concentrations associated with the response were unchanged. This suggested that once in the brain the interaction of CP-141938 with the NK(1) receptor was not affected by P-gp transport. In conclusion, these studies show that brain disposition and centrally mediated in vivo activity of NK(1) antagonists can be profoundly affected by P-gp transport and that such transport should be considered during the design of new agents.
authors.affiliation: Neurosciences Discovery, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton Laboratories, Pfizer, Inc., Groton, Connecticut 06340, USA. Bill_J_Smith@groton.pfizer.com
authors.forename: B J
authors.initials: BJ
authors.lastname: Smith
authors.forename: A C
authors.initials: AC
authors.lastname: Doran
authors.forename: S
authors.initials: S
authors.lastname: McLean
authors.forename: F D
authors.initials: FD
authors.lastname: Tingley
authors.forename: B T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: S M
authors.initials: SM
authors.lastname: Kajiji
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D019450:Genes, MDR / Q000235:genetics; D005849:Gerbillinae; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D000251:Adenosine Triphosphatases; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine