title: 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.
abstract: 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.
authors.affiliation: Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. angela_c_doran@groton.pfizer.com
authors.forename: Angela
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authors.lastname: Doran
authors.forename: R Scott
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authors.forename: Megan A
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authors.forename: Heather
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authors.forename: Cornelis E C A
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authors.lastname: Laperle
authors.forename: Jianhua
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authors.lastname: Liu
authors.forename: Xingrong
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authors.lastname: Logman
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authors.lastname: Maclin
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authors.lastname: Nedza
authors.forename: Frederick
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authors.lastname: Nelson
authors.forename: Emily
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authors.lastname: Olson
authors.forename: Sandhya
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authors.lastname: Rahematpura
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authors.lastname: Raunig
authors.forename: Sabrinia
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authors.lastname: Rogers
authors.forename: Kari
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authors.lastname: Schmidt
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: Mark
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authors.lastname: Szewc
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authors.lastname: Troutman
authors.forename: Elaine
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authors.lastname: Tseng
authors.forename: Meihua
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authors.lastname: Tu
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Van Deusen
authors.forename: Karthik
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authors.lastname: Venkatakrishnan
authors.forename: Gary
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authors.lastname: Walens
authors.forename: Ellen Q
authors.initials: EQ
authors.lastname: Wang
authors.forename: Diane
authors.initials: D
authors.lastname: Wong
authors.forename: Adam S
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authors.forename: Chenghong
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mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002491:Central Nervous System Agents; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3