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. 2012 Jan 25;32(5):874–883. doi: 10.1038/jcbfm.2012.1

Table 1. Summary of the in-silico, in-vitro, and in-vivo data for the (n=36) compounds studied.

Compound name In-silico modelling P-gp score Equilibrium dialysis
 PET
    fP fND fP/fND Parent fraction ROI Blocking agent Blocking dose Kinetic analysis K1 VND
SB-611000a −3.46 0.0668 0.0092 7.27 Model A Cerebellum     Model II 0.07 2.74
SB-611093-AYa −1.26 0.1378 0.0104 13.22 Model C Cerebellum     Model I 0.06 2.34
GSK200742a −1.02 0.2679 0.0402 6.66 Model A Cerebellum     Model I 0.01 0.81
NMSP −0.77 0.1584 0.0483 3.28 Model A Cerebellumb S(−)sulpiride 25.0000 Model II 0.32 3.6
GSK224558 −0.63 0.1234 0.0135 9.14 Model B Cerebellumb GSK224558 0.5000 Model I 0.8 9.66
Loperamidea −0.62 0.1793 0.013 13.83 Model A Cerebellum     Model I 0.05 4.6
GW876008 −0.56 0.0356 0.012 2.97 Model A Cerebellumb GW808990 10.0000 Model II 0.55 5.07
GW692155 −0.53 0.0103 0.001 10.77 Model A Cerebellum     Model II 0.07 2.48
GSK189254 −0.51 0.4646 0.3836 1.21 Model A Cerebellumb GSK189254 0.0500 Model II 0.46 2.46
GSK215083 −0.43 0.288 0.0394 7.31 Model A Cerebellumb GSK215083 0.0050 Model II 0.62 7.59
SB-587828-Aa −0.4 0.0822 0.0107 7.68 Model A Cerebellum     Model I 0.04 1.67
GR205171 −0.27 0.299 0.0646 4.63 Model A Cerebellumb GR205171 0.0625 Model II 0.49 7.68
FLB-457 −0.21 0.4758 0.2114 2.25 Model A Cerebellum     Model II 0.55 3.2
MDL 100907 −0.19 0.4753 0.1201 3.96 Model A Cerebellum     Model I 0.56 7.99
GW775236a −0.03 0.0257 0.0011 22.69 Model A Cerebellumb GR205171 0.0625 Model II 0.24 12.15
GSK991022A 0.03 0.0092 0.101 0.09 Model A Cerebellumb GSK565710 0.5000 Model II 0.03 0.79
Flumazenil 0.09 0.6295 0.5531 1.14 Model A Cerebellum     Model II 0.49 1.24
GW700382 0.1 0.0728 0.0029 24.83 Model B Cerebellumb GR205171 0.0625 Model II 0.47 29.69
GSK219920 0.11 0.0271 0.0109 2.49 Model A Cerebellum     Model II 0.01 0.23
GW194712 0.11 0.0133 0.0018 7.42 Model A Cerebellumb GR205171 0.0625 Model II 0.47 8.34
GW406381 0.21 0.0723 0.0107 6.75 Model A Cerebellum     Model II 0.58 5.44
GSK981352 0.23 0.327 0.147 2.22 Model C Cerebellumb SB-277011 0.5000 Model II 0.61 3.26
GW223994a 0.27 0.124 0.0094 13.21 Model A Cerebellumb GR205171 0.0625 Model II 0.37 8.15
GSK931145 0.36 0.2786 0.0997 2.79 Model A Cerebellumb GSK931145 0.0500 Model II 0.12 1.12
GW679982A 0.36 0.059 0.0098 6 Model A Cerebellum     Model II 0.22 6.77
GW685944 0.36 0.0129 0.0014 9.21 Model A Cerebellum     Model I 0.2 9.49
GW782682 0.37 0.0036 0.0008 4.69 Model B Cerebellum     Model I 0.13 3.48
GSK1018921 0.48 0.0245 0.0415 0.59 Model A Cerebellumb GSK565710 0.5000 Model II 0.08 1
Raclopride 0.54 0.1509 0.1343 1.12 Model A Cerebellum     Model II 0.33 1.11
GSK565710 0.56 0.129 0.0161 8.01 Model A Cerebellumb GSK565710 0.5000 Model II 0.22 5.4
GSK819555 0.58 0.0012 0.0007 1.73 Model A Cerebellum     Model II 0.16 5.11
R-(+)-rolipram 0.59 0.2577 0.1922 1.34 Model A Cerebellumb R(−)Rolipram 0.0100 Model II 0.61 3.47
S-(+)-rolipram 0.59 0.3002 0.1936 1.55 Model A Cerebellumb S(+)Rolipram 0.2500 Model II 0.28 2.63
GW644784 0.71 0.0236 0.0038 6.22 Model A Cerebellum     Model II 0.27 10.11
GSK574734 0.77 0.3185 0.2301 1.38 Model A Cerebellum     Model II 0.22 0.38
PK11195 1.02 0.0658 0.0226 2.9 Model A Cerebellumb PK11195 5.0000 Model II 0.35 4.87

P-gp, P-glycoprotein; ROI, region of interest; PET, positron emission tomography.

The in-silico P-gp score is a metric from a computer model that indicates whether the compound is likely to be a P-gp substrate—negative numbers indicate that the compound is likely to be a substrate with increasingly negative numbers imparting an increased confidence. In-vitro equilibrium dialysis data give the plasma (fP) and tissue (fND) free fraction from plasma and brain homogenate, respectively. For the analysis of the in-vivo PET data, the choice of parent fraction and kinetic analysis method are detailed along with the estimated plasma clearance (K1—mL/min/cm3) and equilibrium partition coefficient (VND—mL/cm3) for cerebellum. Model A—Exponential approach to a constant, Model B—Single exponential, Model C—Two exponential with constrained washout, Model I—One-tissue compartmental analysis, and Model II—Two-tissue compartmental analysis.

a

Compounds identified from analysis of the in-vitro–in-vivo data to be P-gp substrates by post hoc Z-tests (see text).

b

Cerebellum data were obtained from a scan after preadministration of a compound to block specific binding with an associated blocking agent (doses are given in mg/kg).