RT Journal Article SR Electronic T1 THE IMPACT OF P-GLYCOPROTEIN ON THE DISPOSITION OF DRUGS TARGETED FOR INDICATIONS OF THE CENTRAL NERVOUS SYSTEM: EVALUATION USING THE MDR1A/1B KNOCKOUT MOUSE MODEL JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 165 OP 174 DO 10.1124/dmd.104.001230 VO 33 IS 1 A1 Angela Doran A1 R. Scott Obach A1 Bill J. Smith A1 Natilie A. Hosea A1 Stacey Becker A1 Ernesto Callegari A1 Cuiping Chen A1 Xi Chen A1 Edna Choo A1 Julie Cianfrogna A1 Loretta M. Cox A1 John P. Gibbs A1 Megan A. Gibbs A1 Heather Hatch A1 Cornelis E.C.A. Hop A1 Ilana N. Kasman A1 Jennifer LaPerle A1 JianHua Liu A1 Xingrong Liu A1 Michael Logman A1 Debra Maclin A1 Frank M. Nedza A1 Frederick Nelson A1 Emily Olson A1 Sandhya Rahematpura A1 David Raunig A1 Sabrinia Rogers A1 Kari Schmidt A1 Douglas K. Spracklin A1 Mark Szewc A1 Matthew Troutman A1 Elaine Tseng A1 Meihua Tu A1 Jeffrey W. Van Deusen A1 Karthik Venkatakrishnan A1 Gary Walens A1 Ellen Q. Wang A1 Diane Wong A1 Adam S. Yasgar A1 Chenghong Zhang YR 2005 UL http://dmd.aspetjournals.org/content/33/1/165.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics