TABLE 2

In vitro-in vivo extrapolation of transport and metabolism data assuming hepatic clearance is determined by total uptake, metabolism-alone, and extended clearance model

Clearance predictions from pooled hepatocytes substrate-depletion studies were also summarized.

DrugIntrinsic Hepatic Clearance (ml/min per kg)Plasma Hepatic Clearance (ml/min per kg)
ObservedaPredictedObservedaPredicted
Hepatocyte Total UptakeLiver Microsomes MetabolismExtended Clearance ModelHepatocyte Substrate DepletionHepatocyte Total UptakeLiver Microsomes MetabolismExtended Clearance ModelHepatocyte Substrate Depletion
Bromfenac861.6306.331.049.9183.51.300.500.050.080.30
Entacapone1324.659.8234.954.6112.311.501.113.761.011.98
Fluorescein13.33.524.93.21.300.372.210.34
Nateglinide173.855.617.423.234.31.700.610.200.260.38
Diclofenac1220.2391.9160.5255.2213.53.471.340.580.910.77
Fenoprofen60.1151.823.476.769.80.290.700.110.370.34
Gliclazide4.1273.75.00.206.22
Ibuprofen71.7107.326.750.871.20.811.170.320.590.81
Indomethacin102.2236.910.635.428.41.102.310.120.400.32
Isoxicam2.0228.65.70.074.700.20
Ketoprofen59.2120.727.086.420.71.122.070.541.560.42
Meloxicam13.5173.32.016.25.90.111.270.020.130.05
Pioglitazone127.31227.747.1219.872.01.428.610.552.340.83
Piroxicam1.5522.75.90.047.800.14
Pralidoxime8.65.311.54.83.652.424.602.20
Rosiglitazone203.91203.665.1236.6116.00.602.830.200.690.35
R-Warfarin3.9107.10.28.61.90.051.250.000.110.02
Sulfamethoxazole1.011.40.313.16
S-Warfarin9.377.10.416.05.00.120.930.010.200.06
Tolbutamide7.935.21.917.56.10.210.880.050.450.16
Tolcapone1010.4674.677.9239.3131.51.491.040.130.390.22
Clinafloxacin1.838.51.508.71
Naproxen3.994.14.34.224.60.102.160.110.110.62
Thalidomide6.20.53.30.421.92.190.181.250.165.95
Tiagabine11.4281.418.21.579.092.32
  • a Observed plasma hepatic clearance was obtained from Davis et al. (2000), Delrat et al. (2002), Scordo et al. (2002), Obach et al. (2008), Varma et al. (2009), El-Kattan et al. (2016). Observed intrinsic hepatic clearance was calculated from plasma hepatic clearance using eq. 7.