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 Doran, Angela
A1 Obach, R. Scott
A1 Smith, Bill J.
A1 Hosea, Natilie A.
A1 Becker, Stacey
A1 Callegari, Ernesto
A1 Chen, Cuiping
A1 Chen, Xi
A1 Choo, Edna
A1 Cianfrogna, Julie
A1 Cox, Loretta M.
A1 Gibbs, John P.
A1 Gibbs, Megan A.
A1 Hatch, Heather
A1 Hop, Cornelis E.C.A.
A1 Kasman, Ilana N.
A1 LaPerle, Jennifer
A1 Liu, JianHua
A1 Liu, Xingrong
A1 Logman, Michael
A1 Maclin, Debra
A1 Nedza, Frank M.
A1 Nelson, Frederick
A1 Olson, Emily
A1 Rahematpura, Sandhya
A1 Raunig, David
A1 Rogers, Sabrinia
A1 Schmidt, Kari
A1 Spracklin, Douglas K.
A1 Szewc, Mark
A1 Troutman, Matthew
A1 Tseng, Elaine
A1 Tu, Meihua
A1 Van Deusen, Jeffrey W.
A1 Venkatakrishnan, Karthik
A1 Walens, Gary
A1 Wang, Ellen Q.
A1 Wong, Diane
A1 Yasgar, Adam S.
A1 Zhang, Chenghong
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