TABLE 3

Reconstruction of the Kp,brain of the six compounds in cynomolgus monkeys on the basis of the in vitro data

Cynomolgus monkey plasma was spiked with 500-nM concentrations of the compounds and dialyzed against PBS (pH 7.4) at 37°C for 6 hours (n = 3). One-quarter of the diluted brain homogenates of the cynomolgus monkeys was spiked with 260 nM indinavir, 559 nM quinidine, 870 nM loperamide, 3110 nM paclitaxel, 333 nM diazepam, and 117 nM verapamil and dialyzed against ECF buffer (pH 7.4) at 37°C for 6 hours to obtain the homogenate fu,brain (n = 3). The fu,brain (homogenate + pH partition model) was calculated from the homogenate fu,brain in combination with the reported pH partition model (Friden et al., 2011) using the reported pKa values of the compounds (Carvalho-Silva et al., 2004; Friden et al., 2011). The reconstructed Kp,brain values were calculated from the reconstructed Kp,brain ratios (see Table 2) and the fu,plasma and fu,brain (homogenate + pH partition model) values using eq. 3. Each value represents the mean ± S.E.M. The S.E.M. was calculated according to the law of propagation of error.

Compoundfu,plasmafu,brainReconstructed 
Kp,brain
HomogenateHomogenate + pH Partition Model
ml/g brain
Indinavir0.643 ± 0.0440.297 ± 0.0210.261 ± 0.0180.442 ± 0.044
Quinidine0.0591 ± 0.00150.0621 ± 0.00490.0219 ± 0.00170.254 ± 0.036
Loperamide0.0776 ± 0.00520.0103 ± 0.00120.00360 ± 0.000421.32 ± 0.18
Paclitaxel0.125 ± 0.0060.0151 ± 0.00140.0151 ± 0.00141.08 ± 0.15
Diazepam0.0523 ± 0.00250.0356 ± 0.00140.0356 ± 0.00141.54 ± 0.23
Verapamil0.211 ± 0.0130.0416 ± 0.00310.0145 ± 0.00112.83 ± 0.28