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.
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.
Doran
Angela
A
Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. angela_c_doran@groton.pfizer.com
Obach
R Scott
RS
Smith
Bill J
BJ
Hosea
Natilie A
NA
Becker
Stacey
S
Callegari
Ernesto
E
Chen
Cuiping
C
Chen
Xi
X
Choo
Edna
E
Cianfrogna
Julie
J
Cox
Loretta M
LM
Gibbs
John P
JP
Gibbs
Megan A
MA
Hatch
Heather
H
Hop
Cornelis E C A
CE
Kasman
Ilana N
IN
Laperle
Jennifer
J
Liu
Jianhua
J
Liu
Xingrong
X
Logman
Michael
M
Maclin
Debra
D
Nedza
Frank M
FM
Nelson
Frederick
F
Olson
Emily
E
Rahematpura
Sandhya
S
Raunig
David
D
Rogers
Sabrinia
S
Schmidt
Kari
K
Spracklin
Douglas K
DK
Szewc
Mark
M
Troutman
Matthew
M
Tseng
Elaine
E
Tu
Meihua
M
Van Deusen
Jeffrey W
JW
Venkatakrishnan
Karthik
K
Walens
Gary
G
Wang
Ellen Q
EQ
Wong
Diane
D
Yasgar
Adam S
AS
Zhang
Chenghong
C
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
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