TABLE 1

Parameter estimates from the modeling of the drug depletion data

ParameterPropranololPrednisolonePhenacetinLidocaineIbuprofenDiclofenac
Individual-donor data
 CLint(u)a3.88 (28.6%)0.81 (14.7%)8.91 (12.7%)4.38 (12.9%)5.02 (16.2%)17.80 (16.8%)
 IDVb66.8% (40.9%)29.3% (58.1%)24.1% (80.4%)28.5% (38.1%)32.6% (44.9%)36.2% (71.5%)
 IWVb32.9% (62.7%)21.5% (70.0%)26.1% (65.2%)11.3% (26.5%)30.7% (55.8%)6.0% (120.9%)
 RVb21.6% (56.6%)10.3% (25.8%)14.2% (69.8%)8.4% (34.0%)9.6% (29.3%)20.0% (26.2%)
Pooled hepatocytes data
 CLint(u)a6.34 (5.9%)0.91 (4.0%)9.67 (17.4%)4.24 (3.6%)3.54 (33.3%)18.60 (14.4%)
 IWVb9.6% (50.4%)c30.7% (41.5%)5.9% (43.7%)62.5% (40.0%)23.6% (54.4%)
 RVb19.7% (41.1%)11.4% (32.0%)9.5% (40.4%)6.9% (14.4%)7.5% (15.8%)16.3% (28.6%)
Individual-donor/pooled hepatocytes
 CLint(u) ratiod0.61 (0.27, 0.97)0.89 (0.63, 1.16)0.92 (0.61, 1.47)1.03 (0.77, 1.31)1.42 (0.75, 4.20)0.96 (0.60, 1.48)
  • a The typical unbound intrinsic clearance [CLint(u)] for each drug is reported in μl/min/106 cells.

  • b Interdonor variability in unbound intrinsic clearance (IDV), interwell variability in unbound intrinsic clearance (IWV), and the residual variability in the observed data (RV) are reported in terms of CV%, which was calculated as Graphic, where “variance” is the estimate of ω2, π2, and σ2 for IDV, IWV, and RV, respectively (see Materials and Methods). Values in parentheses correspond to relative standard errors calculated as Graphic.

  • c Interwell variability could not be estimated and was fixed to 0.

  • d Ratio of CLint(u) determined in the individual donor data to the CLint(u) determined in the pooled hepatocytes data. Values in parentheses correspond to 95% confidence intervals of this ratio, calculated using Fieller’s theorem and assuming normality of the CLint(u) estimators. The average CLint(u) ratio across all compounds is 0.97.