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

• DOI: 10.1124/dmd.104.001230
• Publication Date: 2004-10-23T00:24:47Z
• Authors: Angela Doran; R. Scott Obach; Bill J. Smith; Natilie A. Hosea; Stacey Becker; Ernesto Callegari; Cuiping Chen; Xi Chen; Edna Choo; Julie Cianfrogna; Loretta M. Cox; John P. Gibbs; Megan A. Gibbs; Heather Hatch; Cornelis E.C.A. Hop; Ilana N. Kasman; Jennifer LaPerle; JianHua Liu; Xingrong Liu; Michael Logman; Debra Maclin; Frank M. Nedza; Frederick Nelson; Emily Olson; Sandhya Rahematpura; David Raunig; Sabrinia Rogers; Kari Schmidt; Douglas K. Spracklin; Mark Szewc; Matthew Troutman; Elaine Tseng; Meihua Tu; Jeffrey W. Van De...; Karthik Venkatakr...; Gary Walens; Ellen Q. Wang; Diane Wong; Adam S. Yasgar; Chenghong Zhang
• Keywords: Knockout mouse; Active metabolite; P-glycoprotein; Ratón

Thirty-two structurally diverse drugs used for the treatment of various conditions central nervous system (CNS), along with two active metabolites, and eight non-CNS were measured in brain, plasma, cerebrospinal fluid P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, data compared corresponding obtained wild-type mice. Total brain-to-plasma (B/P) ratios CNS agents ranged from 0.060 to 24. Of 34 CNS-active agents, only 7 demonstrated B/P area under plasma concentration curve between P-gp mice that did not differ significantly unity. Most remaining 1.1- 2.6-fold greater versus Three, risperidone, its metabolite 9-hydroxyrisperidone, metoclopramide, showed marked differences (6.6- 17-fold). Differences fluid/plasma animals correlated. Through use this model, it appears most demonstrate at least some P-gp-mediated transport can affect brain concentrations. However, impact majority is probably minor. The example risperidone illustrates even good substrates still be clinically useful agents. such unbound concentrations may need than values projected using receptor affinity achieve adequate occupancy effect.