PT  - JOURNAL ARTICLE
AU  - Doran, Angela
AU  - Obach, R. Scott
AU  - Smith, Bill J.
AU  - Hosea, Natilie A.
AU  - Becker, Stacey
AU  - Callegari, Ernesto
AU  - Chen, Cuiping
AU  - Chen, Xi
AU  - Choo, Edna
AU  - Cianfrogna, Julie
AU  - Cox, Loretta M.
AU  - Gibbs, John P.
AU  - Gibbs, Megan A.
AU  - Hatch, Heather
AU  - Hop, Cornelis E.C.A.
AU  - Kasman, Ilana N.
AU  - LaPerle, Jennifer
AU  - Liu, JianHua
AU  - Liu, Xingrong
AU  - Logman, Michael
AU  - Maclin, Debra
AU  - Nedza, Frank M.
AU  - Nelson, Frederick
AU  - Olson, Emily
AU  - Rahematpura, Sandhya
AU  - Raunig, David
AU  - Rogers, Sabrinia
AU  - Schmidt, Kari
AU  - Spracklin, Douglas K.
AU  - Szewc, Mark
AU  - Troutman, Matthew
AU  - Tseng, Elaine
AU  - Tu, Meihua
AU  - Van Deusen, Jeffrey W.
AU  - Venkatakrishnan, Karthik
AU  - Walens, Gary
AU  - Wang, Ellen Q.
AU  - Wong, Diane
AU  - Yasgar, Adam S.
AU  - Zhang, Chenghong
TI  - 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
AID  - 10.1124/dmd.104.001230
DP  - 2005 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 165--174
VI  - 33
IP  - 1
4099  - http://dmd.aspetjournals.org/content/33/1/165.short
4100  - http://dmd.aspetjournals.org/content/33/1/165.full
SO  - Drug Metab Dispos2005 Jan 01; 33
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