TABLE 2

 Kinetic parameters for drug uptake in suspended hepatocytes

Data are presented as means.

DrugsPSinfPSu,inf (+)cfBPSvitroeu,infDispersion modelWell-stirred model
0% HSAa5% HSAb0% HSA5% HSAfBd0% HSA5% HSAR valueffBCLh,u,int,allvivogRatioh (in vivo/in vitro)fBPSvitrou,inf ⋅ SF at 5% HAS fBCLh,u,int,allvivogRatioh (in vivo/in vitro)fBPSvitrou,inf ⋅ SF at 5% HAS
μl/min/106 cellsμl/min/106 cellsml/min/kgml/min/kgml/min/kggml/min per kilogramml/min per kilogram
Pitavastatin36.20.49336.288.30.009321.042.542.4414.15.576.2018.07.118.11
Atorvastatin24.22.1624.277.00.04673.4811.13.1825.32.2827.139.13.5335.4
Rosuvastating4.010.9834.019.940.1952.415.982.4820.63.4414.629.24.8919.1
Fluvastatin62.11.7262.14240.006901.329.036.8327.33.0222.143.64.8328.8
Cerivastatin77.52.3177.52400.01273.029.373.105.960.63622.96.590.70329.9
Pravastatin3.55NA3.55NA1.0011.0NANA22.9NANA33.9NANA
Glibenclamide32.20.15532.21730.001710.1700.9125.382.472.712.232.582.832.91
Valsartan1.870.05141.871190.003010.01741.1163.80.6980.6302.710.7010.6333.54
Repaglinide39.22.4839.22070.01091.326.955.2719.02.7217.026.33.7822.2
Bosentan23.21.2423.21130.009810.7033.414.863.140.9198.343.310.96910.9
Nateglinide12.50.28212.543.90.009940.3821.353.523.372.503.293.582.664.30
  • CLh,u,int,all, the in vivo unbound hepatic intrinsic clearance; fB, blood-unbound fraction; NA, not applicable; PSinf, the hepatic uptake clearance for total drug; PSu,inf, the hepatic uptake clearance for unbound drug; SF, Scaling factor.

  • a Obtained mean value from the suspended hepatocyte uptake study without HSA (Embedded Image

  • b Predicted by Tsao’s model in the presence of 5% HSA using the observed data at 0–1% HSA (eq. 5; Table 1).

  • c Calculated by dividing PSinf by fu, where fu is 1 in the absence of HSA.

  • d Calculated by dividing fp by RB, where RB is the blood partitioning.

  • e Scaled-up from in vitro PSu,inf (+) using the following physiologic scaling factors (1.2 × 108 cells/g of liver, 25.7 g of liver/kg of body weight).

  • f R values, the “albumin-mediated” uptake factor, was calculated as the ratio of fBPSvitrou,inf at 0% HSA to that at 5% HSA.

  • g These data were calculated using the dispersion model or the well-stirred model using the reported hepatic clearance. The details are shown in Supplemental Table S3.

  • h Calculated by fBCLvivoh,u,int,all / fBPSvitrou,inf at 5% HSA; the mean value is 2.44 for the dispersion model and 3.19 for the well-stirred model, which was used as the scaling factor (SF).