P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists

CP-122721 and CP-141938 are potent and selective neurokinin-1 (NK1) recepto r antagonists with very different brain disposition and potency in models o f centrally mediated activity. These investigations sought to determine whe ther differences in potency were related to differences in P-glycoprotein ( P-gp) transport at the blood-brain barrier. Both compounds stimulated ATPas e activity of human recombinant MDR1 with similar kinetic parameters. Cell- associated drug concentrations of CP-141938 were 9.4-fold lower in KBV1 cel ls expressing P-gp compared with KB3.1 control cells. In Madin-Darby canine kidney (MDCK) cells expressing human MDR1, asymmetric transport of CP-1419 38 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 t ransport, the differences in brain/plasma ratio between mdr1a/b(-/-) and FV B 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 ef fects of these agents was evaluated using GR73632-incluced foot tapping in gerbils as a model to measure centrally mediated NK1 antagonism. When gerbi ls were pretreated with the P-gp inhibitor MS-073 (50 mg/kg s.c.), there wa s 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, th e brain/plasma ratio for CP-122721 was unaffected by MS-073 pretreatment, w hereas the brain/plasma ratio for CP-141938 brain concentrations increased 13-fold. This suggested that P-gp efflux influences the brain disposition a nd pharmacologic activity of CP-141938, but not CP-122721. Complete respons e 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-1419 38 were shifted to the left in the presence of MS-073, yet brain concentrat ions associated with the response were unchanged. This suggested that once in the brain the interaction of CP-141938 with the NK1 receptor was not aff ected by P-gp transport. In conclusion, these studies show that brain dispo sition and centrally mediated in vivo activity of NK1 antagonists can be pr ofoundly affected by P-gp transport and that such transport should be consi dered during the design of new agents.