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
  • 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).