TABLE 2

Comparison of in vivo Ctissue/Cplasma on the brain and testis distribution and the Kp ratios determined by PS products of P-gp and Bcrp

PS products for the efflux of Bcrp and P-gp (PSBcrp and PSP-gp) can be obtained by the method of least squares for the sum of squares of the residual between in vivo the Ctissue/Cplasma in the knockout mice to wild-type mice on the brain and testis distribution and Kp ratio calculated by eqs. 7 to 9, if the PS product for the efflux across the blood-side membrane is unity. In vivo the Ctissue/Cplasma was calculated from the data in Fig. 4. PSBcrp and PSP-gp are shown as the mean value and S.D. except for dasatinib.

CompoundTissuePSBcrpPSP-gpRMdr1a/1b(−/−)RBcrp(−/−)RMdr1a/1b(−/−)/Bcrp(−/−)
ErlotinibBrain1.89 ± 0.015.63 ± 0.01Calculated2.951.288.52
In vivo2.951.298.52
Testis0.933 ± 0.2794.32 ± 0.38Calculated3.231.186.25
In vivo3.291.596.24
FlavopiridolBrain3.07 ± 0.0210.1 ± 0.0Calculated3.481.2814.2
In vivo3.491.2714.2
Brainc2.83 ± 0.71e3.50 ± 0.71eCalculated1.911.637.33
In vivo1.671.297.35
Brainc2.73 ± 0.69f3.15 ± 0.70fCalculated1.841.666.87
In vivo1.581.336.89
Testis0.948 ± 0.4235.32 ± 0.65Calculated3.731.157.27
In vivo3.801.877.25
MitoxantroneBrain3.14 ± 0.553.86 ± 0.56Calculated1.931.658.00
In vivo1.751.408.01
Testis1.50 ± 0.412.00 ± 0.41Calculated1.801.504.50
In vivo1.991.774.47
DasatinibaBrain1g7gCalculated519
In vivo419
ImatinibBrainc5.31 ± 0.42e21.9 ± 0.5eCalculated4.471.2328.2
In vivo4.450.9428.2
Brainc13.2 ± 1.3f49.4 ± 1.3fCalculated4.491.2663.6
In vivo4.460.8663.6
Braind4.4 ± 1.1h7.9 ± 1.1hCalculated2.51.513.3
In vivo2.31.013.3
Braind5.8 ± 3.2i5.8 ± 3.2iCalculated1.91.912.6
In vivo1.01.012.6
LapatinibbBrain12.2 ± 0.5j26.8 ± 0.5jCalculated3.021.4440.0
In vivo3.001.3340.0
Brain9.55 ± 0.76k32.0 ± 0.8kCalculated4.031.2942.5
In vivo4.001.0042.5
PrazosincBrain1.72 ± 0.16e2.51 ± 0.17eCalculated1.931.495.23
In vivo1.861.385.24
Brain1.63 ± 0.53f2.52 ± 0.54fCalculated1.951.465.15
In vivo1.751.105.18
  • a Chen et al. (2009).

  • b Polli et al. (2009).

  • c Zhou et al. (2009).

  • d Oostendorp et al. (2009).

  • e Determined 0.5 h after subcutaneous administration.

  • f Determined 2 h after subcutaneous administration.

  • g Determined 2 h after oral administration.

  • h Determined 1 h after oral administration.

  • i Determined 4 h after oral administration.

  • j Determined 24 h after constant infusion at a rate of 0.3 mg/h/kg.

  • k Determined 24 h after constant infusion at a rate of 3 mg/h/kg.