TABLE 1

P-gp activities, unbound fractions, AUC, and AUC ratios of seven model compounds

Class I
Class II
Theobromine
Theophylline
Caffeine
Fluoxetine
Propranolol
CP-141938
NFPS
BPko/BPwta 1.8b 1.3b 1.1c 1.5c 1.5b 50d 2.1b
In situ PSe (ml/h/kg) 23 31 223 619 1043 6.4 31
Plasma unbound fractionf 0.92 0.29 0.96 0.060 0.15 0.56 0.041
Brain unbound fractionb (Slice) 0.62 0.31 0.71 0.0027 0.019 0.11 0.011
Brain unbound fractionf (Homogenate) 0.61 0.39 1.1 0.00094 0.036 0.22 0.0017
AUC(Plasma, 0-∞) (ng · h/ml) 4670 6990 3250 195 237 296 1480
AUC(CSF, 0-∞) (ng · h/ml) 5790 1420 3140 13.3 48.0 18.9 7.59
AUC(Brain, 0-∞) (ng · hr/ml) 2540 1910 2010 5140 3880 98.8 648
Cu,brain/CCSFg (Slice) 0.27 0.42 0.45 1.0 1.5 0.57 0.94
Cu,brain/Cu, plasmag (Slice) 0.37 0.29 0.46 1.2 2.1 0.066 0.12
Cu,brain/CCSFh (Homogenate) 0.27 0.52 0.70 0.36 2.9 1.1 0.15
Cu,brain/Cu,plasmah (Homogenate) 0.36 0.37 0.71 0.41 3.9 0.13 0.018
CCSF/Cu,plasma
 1.3
0.70
1.0
1.1
1.4
0.11
0.13

  • ↵ a BPko and BPwt represent the brain-to-plasma concentration ratio in mdr1a/1b gene knockout and FVB mice, respectively.

  • ↵ b Becker and Liu (2006): unbound fraction in brain tissue determined using brain slices.

  • ↵ c Doran et al (2005).

  • ↵ d Smith et al (2001).

  • ↵ e Liu et al. (2004): BBB permeability-surface area product, PS.

  • ↵ f Liu et al. (2005): unbound fraction in plasma determined using equilibrium dialysis.

  • ↵ g Cu,brain: the brain unbound fraction was determined from the brain slice method.

  • ↵ h Cu,brain: the brain unbound fraction was determined from the brain homogenate method.