TABLE 1

In vitro process clearances, in vitro Kpuu, and human drug exposure

ECM classes were derived as described in Fig. 2. Unbound extracellular (systemic and hepatic inlet) and intrahepatic concentrations were calculated as described in Materials and Methods, and all required pharmacokinetic parameters and corresponding literature references are summarized in Supplemental Tables 1–3. Literature references for BSEP IC50 values are provided in Supplemental Table 4; presented data represent the lowest available IC50 value.

Drug CompoundsHepatic Process ClearancesIn Vitro KpuuUnbound Extracellular ConcentrationsUnbound Intrahepatic ConcentrationsBSEP Inhibition
PSinf,actPSinf,pasaCLint,metCLint,secCsys,uCinlet,uChep,sys,uChep,inlet,uIC50
ml/min/kgml/min/kgml/min/kgml/min/kgµMµMµMµMµM
ECM class 1
 Ketoconazole0.058.597.429.60.320.16610.29410.05320.09412.9
ECM class 2
 Imatinib0.0300.940.93.20.870.47811.15340.41591.0035<10
 Verapamil0.0258.2127.78.10.660.06070.23980.04010.158320.5
ECM class 3
 Atazanavir71.820.81240.581.90.071.16532.35000.08160.16453.1
 Atorvastatin140.357.764.611.11.480.02260.08190.03340.121215.0
 Cyclosporine A113.241.977.69.11.210.05120.13710.06200.16590.4
 Erythromycin10.220.399.78.90.241.00831.13340.24200.27204.1
 Ibuprofen22.221.734.210.30.663.92895.18802.59313.4241598.6
 Lovastatin acid165.1145.5459.000.510.00500.01140.00260.005819.3
 Rosiglitazone45.646.698.100.640.00360.00480.00230.00311.9
 Simvastatin acid116.1297.9769.21.50.390.00080.09170.00030.035820.9
ECM class 4
 Bosentan (125 mg BID)30.761.516.20.81.170.06630.09600.07760.112322.0
 Bosentan (1000 mg BID)30.761.516.20.81.170.46440.93120.54331.089522.0
 Cerivastatin221.5243.846.901.600.00030.00050.00050.000818.8
 Fluvastatin218.7325.5146.801.150.00520.01330.00600.015336.1
 Glibenclamide66.4109.641.16.31.120.00940.01330.01050.01491.5
 Pitavastatin364.3258.817.702.250.01110.03920.02450.088242.2
 Pravastatin58.036.00.92.12.410.07160.79990.17261.9278268.4
 Rosuvastatin27.224.81.55.81.620.00920.06700.01490.1085197.6
  • BID, twice daily.

  • a In the present study, PSeff was assumed to occur only via passive diffusion and to be equal to PSinf,pas (PSeff = PSinf,pas).