Compound | In Vivo CLnonrenal | In Vitro Predicted CLh from Three Donors | |||||||
---|---|---|---|---|---|---|---|---|---|
Donor RTM | Donor 1 | Donor 3 | Mean ± SD | ||||||
fu | w/o fu | fu | w/o fu | fu | w/o fu | fu | w/o fu | ||
ml/min per kg | |||||||||
Low clearancea | |||||||||
Warfarin | 0.081 | 0.042 | 3.49 | 0.026 | 2.29 | 0.040 | 3.36 | 0.036 ± 0.009 | 3.05 ± 0.66 |
Meloxicam | 0.12 | 0.049 | 5.64 | 0.019 | 2.70 | 0.012 | 1.84 | 0.027 ± 0.020 | 3.80 ± 2.34 |
Tolbutamide | 0.31 | 0.39 | 5.12 | 0.23 | 2.55 | 0.25 | 3.60 | 0.29 ± 0.09 | 3.76 ± 1.29 |
Diazepam | 0.53 | 0.21 | 8.54 | 0.19 | 7.98 | 0.15 | 6.66 | 0.18 ± 0.031 | 7.73 ± 0.97 |
Alprazolam | 0.61 | 1.43 | 4.19 | 0.784 | 2.47 | 1.09 | 3.33 | 1.10 ± 0.32 | 3.33 ± 0.86 |
Glimepiride | 1.12 | 0.590 | 17.9 | 0.36 | 16.3 | 0.24 | 14.6 | 0.40 ± 0.18 | 16.27 ± 1.65 |
Theophylline | 1.13 | 1.13 | 2.48 | 1.15 | 2.59 | 1.48 | 3.29 | 1.25 ± 0.20 | 2.79 ± 0.44 |
Prednisolone | 1.44 | 1.80 | 5.39 | 1.26 | 4.02 | 2.00 | 5.88 | 1.69 ± 0.38 | 5.10 ± 0.96 |
Riluzole | 2.05 | 3.13 | 18.8 | 3.09 | 18.8 | 0.81 | 14.1 | 2.35 ± 1.33 | 17.23 ± 2.71 |
Voriconazole | 3.80 | 5.92 | 9.92 | 7.99 | 12.5 | 7.57 | 12.03 | 7.16 ± 1.1 | 11.48 ± 1.37 |
Within 2-fold (%) | 70 | 0 | 50 | 0 | 60 | 0 | 60 | 0 | |
Within 3-fold (%) | 100 | 20 | 70 | 20 | 70 | 10 | 90 | 10 | |
Intermediate clearanceb | |||||||||
Risperidone | 5.16 | 4.25 | 14.6 | 5.15 | 15.7 | 1.56 | 8.81 | 3.65 ± 1.87 | 13.0 ± 3.7 |
Flecainide | 5.82 | 1.31 | 2.99 | 0.950 | 2.27 | 0.621 | 1.52 | 0.96 ± 0.34 | 2.26 ± 0.74 |
Atomoxetinec | 7.05 | 2.00 | 18.6 | 1.49 | 17.9 | 0.37 | 12.1 | 1.29 ± 0.83 | 16.2 ± 3.6 |
Diclofenac | 7.67 | 1.99 | 20.0 | 1.16 | 19.3 | 1.05 | 19.2 | 1.40 ± 0.51 | 19.6 ± 0.44 |
Atazanavir | 8.13 | 12.3 | 19.1 | 10.4 | 18.4 | 8.85 | 17.6 | 10.5 ± 1.7 | 18.3 ± 0.6 |
Midazolam | 8.59 | ND | ND | 4.52 | 19.6 | 4.52 | 19.3 | 4.52 | 19.3 |
Lidocaine | 10.7 | 7.27 | 13.3 | 6.27 | 12.3 | 5.10 | 10.9 | 6.21 ± 1.09 | 12.2 ± 1.21 |
Within 2-fold (%) | 50 | 33 | 57 | 14 | 43 | 43 | 57 | 14 | |
Within 3-fold (%) | 50 | 100 | 57 | 86 | 43 | 71 | 57 | 100 |
ND, not determined.
↵a Low clearance is CLnonrenal <5 ml/min per kg.
↵b Intermediate clearance is 5 ml/min per kg < CLnonrenal <15 ml/min per kg.
↵c The in vivo clearance value reported for extensive metabolizers was used since the incidence of phenotype is highest in the population. Predicted CLh values for both corrected (CLh,w/fu) and not corrected (CLh, w/o/fu) plasma protein binding were derived from the average of at least two replicates. Categorization of fold prediction was defined as follows: for ±2-fold, 0.45 ≤ value ≤2.1; ±3-fold, 0.325 ≤ value ≤3.1.