Journal article
P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists
The Journal of pharmacology and experimental therapeutics, Vol.298(3), pp.1252-1259
09/2001
DOI: 10.1016/S0022-3565(24)29500-8
PMID: 11504828
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.
Details
- Title: Subtitle
- P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists
- Creators
- Bill J Smith - 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.comAngela C DoranStafford McLeanF David Tingley IIIBrian T O’NeillShama M Kajiji
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.298(3), pp.1252-1259
- DOI
- 10.1016/S0022-3565(24)29500-8
- PMID
- 11504828
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Language
- English
- Date published
- 09/2001
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094734202771
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