Table 2

Plasma and brain concentrations of unchanged drug in mdr1a(−/−) and (+/+) CF-1 mice subpopulations after intravenous injection of indinavir, ritonavir, diazepam, compound X, vinblastine, and compounds A and D

mdr1a(−/−)mdr1a (+/+)Ratio (−/−):(+/+)
Indinavir (10 mg/kg)
 15 min
  Plasma2.99  ± 0.153.28  ± 0.600.91
  Brain0.740.511.45
  Kp,brain0.250.161.59
 30 min
  Plasma0.78  ± 0.400.48  ± 0.151.63
  Brain0.750.302.50
  Kp,brain0.960.631.54
 60 min
  Plasma0.20  ± 0.350.09  ± 0.082.22
  Brain0.350.201.75
  Kp,brain1.752.220.79
 AUCbrain (0–60 min)33.2317.401.91
Ritonavir (10 mg/kg)
 15 min
  Plasma6.69  ± 1.326.27  ± 1.381.07
  Brain1.620.246.68
  Kp,brain0.240.046.26
 30 min
  Plasma3.29  ± 0.553.88  ± 0.190.85
  Brain1.840.247.74
  Kp,brain0.560.069.11
 60 min
  Plasma0.77  ± 0.131.82  ± 0.130.42
  Brain1.770.305.86
  Kp,brain2.310.1713.97
 AUCbrain (0–60 min)92.2013.506.83
Diazepam (2 mg/kg)
 15 min
  Plasma0.27  ± 0.060.22  ± 0.021.18
  Brain0.260.340.96
  Kp,brain0.991.520.65
 30 min
  Plasma0.10  ± 0.020.11  ± 0.100.95
  Brain0.100.100.93
  Kp,brain0.950.980.98
 60 min
  Plasma0.04  ± 0.010.04  ± 0.031.08
  Brain0.040.041.13
  Kp,brain1.081.051.04
 AUCbrain (0–60 min)6.717.970.84
Compound X (2 mg/kg)
 15 min
  Plasma1.00  ± 0.270.80  ± 0.091.25
  Brain0.460.095.14
  Kp,brain0.460.114.12
 30 min
  Plasma0.53  ± 0.030.38  ± 0.131.40
  Brain0.330.047.79
  Kp,brain0.620.115.55
 60 min
  Plasma0.12  ± 0.050.14  ± 0.080.86
  Brain0.080.023.86
  Kp,brain0.670.154.50
 AUCbrain (0–60 min)15.522.625.95
Vinblastine (6 mg/kg)
 15 min
  Plasma0.31  ± 0.140.34  ± 0.040.91
  Brain0.330.065.50
  Kp,brain1.060.186.03
 30 min
  Plasma0.23  ± 0.030.29  ± 0.040.79
  Brain0.510.077.29
  Kp,brain2.220.249.19
 60 min
  Plasma0.21  ± 0.010.23  ± 0.040.88
  Brain0.700.097.78
  Kp,brain3.410.398.84
 AUCbrain (0–60 min)26.933.837.04
Compound A (10 mg/kg)
 15 min
  Plasma2.39  ± 0.362.32  ± 0.371.03
  Brain7.440.4118.15
  Kp,brain3.110.1817.61
 30 min
  Plasma1.14  ± 0.091.61  ± 0.040.71
  Brain6.630.6410.36
  Kp,brain5.820.4014.59
 60 min
  Plasma0.34  ± 0.060.21  ± 0.071.63
  Brain3.320.2314.43
  Kp,brain9.851.118.87
 AUCbrain (0–60 min)310.5824.0012.94
Compound D (20 mg/kg)
 15 min
  Plasma1.34  ± 0.232.07  ± 0.280.65
  Brain0.880.156.02
  Kp,brain0.650.079.28
 30 min
  Plasma1.32  ± 0.291.60  ± 0.030.82
  Brain1.040.1010.38
  Kp,brain0.790.0612.61
 60 min
  Plasma0.92  ± 0.151.00  ± 0.090.92
  Brain0.950.0519.04
  Kp,brain1.030.0520.69
 AUCbrain (0–60 min)50.825.199.79

After intravenous injection, mice were killed at 15, 30, and 60 min and plasma and brain concentrations of unchanged drug were measured by either high performance liquid chromatography or LC-MS. Three mice were analyzed in each group. Plasma concentrations (in μg/ml) are shown as mean ± S.D. Brain concentrations of each compound in the pooled samples of three mice were measured and expressed in μg/g of brain. Kp,brain represents the brain-to-plasma concentration ratio. AUCbrain (0–60 min) was calculated using trapezoidal rule and is shown in μg/g · min.