Vol. 298, Issue 3, 1252-1259, September 2001

P-Glycoprotein Efflux at the Blood-Brain Barrier Mediates Differences in Brain Disposition and Pharmacodynamics between Two Structurally Related Neurokinin-1 Receptor Antagonists

Bill J. Smith, Angela C. Doran, Stafford McLean, F. David Tingley, III, Brian T. O'Neill and Shama M. Kajiji

Neurosciences Discovery, Departments of Pharmacokinetics, Dynamics and Metabolism (B.J.S., A.C.D.), Neurosciences Biology (S.M., F.D.T.), Neurosciences Medicinal Chemistry (B.T.O.), and Cancer Discovery Biology (S.M.K.), Pfizer Global Research and Development, Groton Laboratories, Pfizer, Inc., Groton, Connecticut

CP-122721 and CP-141938 are potent and selective neurokinin-1 (NK₁) 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 NK₁ 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 NK₁ receptor was not affected by P-gp transport. In conclusion, these studies show that brain disposition and centrally mediated in vivo activity of NK₁ antagonists can be profoundly affected by P-gp transport and that such transport should be considered during the design of new agents.