PT  - JOURNAL ARTICLE
AU  - Bill J. Smith
AU  - Angela C. Doran
AU  - Stafford McLean
AU  - F. David Tingley III
AU  - Brian T. O'Neill
AU  - Shama M. Kajiji
TI  - P-Glycoprotein Efflux at the Blood-Brain Barrier Mediates Differences in Brain Disposition and Pharmacodynamics between Two Structurally Related Neurokinin-1 Receptor Antagonists
DP  - 2001 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1252--1259
VI  - 298
IP  - 3
4099  - http://jpet.aspetjournals.org/content/298/3/1252.short
4100  - http://jpet.aspetjournals.org/content/298/3/1252.full
SO  - J Pharmacol Exp Ther2001 Sep 01; 298
AB  - 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 NK1antagonism. 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. The American Society for Pharmacology and Experimental Therapeutics