TABLE 3

Unbound fractions in plasma and brain, and reconstruction of Kp brain from in vitro data for 11 P-gp substrates

To determine the unbound fractions in mouse brain (fu,brain), mouse brain slices (500 μm) were incubated in ECF buffer, pH 7.4, containing 14.6 nM quinidine, 3.11 nM loperamide, 21.7 nM digoxin, 113 nM risperidone, 36.4 nM indinavir, 127 nM dexamethasone, 1.78 nM vinblastine, 3.25 nM paclitaxel, 38.9 nM verapamil, 0.274 nM loratadine, and 71.1 nM diazepam at 37°C for 6 h (n = 3). The reconstructed Kp brain values were calculated from the reconstructed Kp brain ratios (see Table 2), the unbound fractions in mouse brain, and the reported unbound fractions in mouse plasma according to equation 11. Each value for fu,plasma represents the mean ± S.D. Each value for fu,brain and reconstructed Kp brain represents the mean ± S.E.M. The S.E.M. for reconstructed Kp brain was calculated according to the law of propagation of error.

Substratefu, plasmafu,brainReconstructed
Kp brain
ml/g of brain
Quinidine0.160 ± 0.030a0.0409 ± 0.00510.127 ± 0.012
Loperamide0.0230 ± 0.0050a0.00479 ± 0.000710.206 ± 0.017
Digoxin0.330 ± 0.020a0.0386 ± 0.00260.515 ± 0.052
Risperidone0.204 ± 0.011b0.0555 ± 0.00560.371 ± 0.029
Indinavir0.0580 ± 0.0070a0.0817 ± 0.00500.0793 ± 0.0076
Dexamethasone0.272 ± 0.014a0.187 ± 0.0120.130 ± 0.009
Vinblastine>0.09a0.00588 ± 0.00072>1.32
Paclitaxel0.0210 ± 0.0020a0.00488 ± 0.000710.374 ± 0.039
Verapamil0.110 ± 0.030a0.0257 ± 0.00170.345 ± 0.031
Loratadine0.00450 ± 0.00017a0.00208 ± 0.000121.27 ± 0.09
Diazepam0.0980 ± 0.0070b0.0579 ± 0.00721.95 ± 0.10
  • a Kalvass et al. (2007).

  • b Maurer et al. (2005).