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Departments of Pharmacokinetics, Dynamics, and Drug Metabolism (A.D., R.S.O., B.J.S., N.A.H., S.B., E.Ca., C.C., X.C., E.Ch., J.C., L.M.C., J.P.G., H.H., C.E.C.A.H., I.N.K., J.L., J.H.L., X.L., M.L., D.M., F.M.N., F.N., E.O., S.Ra., S.Ro., K.S., D.K.S., M.S., M.Tr., E.T., J.W.V., K.V., E.Q.W., D.W., A.S.Y., C.Z.), Exploratory Medicinal Sciences (M.Tu), Clinical Pharmacokinetics and Pharmacodynamics (M.A.G.), Market Assessment (G.W.), and Non-Clinical Biostatistics (D.R.), Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut
Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with corresponding data obtained in wild-type mice. Total brain-to-plasma (B/P) ratios for the CNS agents ranged from 0.060 to 24. Of the 34 CNS-active agents, only 7 demonstrated B/P area under the plasma concentration curve ratios between P-gp knockout and wild-type mice that did not differ significantly from unity. Most of the remaining drugs demonstrated 1.1- to 2.6-fold greater B/P ratios in P-gp knockout mice versus wild-type mice. Three, risperidone, its active metabolite 9-hydroxyrisperidone, and metoclopramide, showed marked differences in B/P ratios between knockout and wild-type mice (6.6- to 17-fold). Differences in B/P ratios and cerebrospinal fluid/plasma ratios between wild-type and knockout animals were correlated. Through the use of this model, it appears that most CNS-active agents demonstrate at least some P-gp-mediated transport that can affect brain concentrations. However, the impact for the majority of agents is probably minor. The example of risperidone illustrates that even good P-gp substrates can still be clinically useful CNS-active agents. However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect.
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