Km | Vmax | Pdif | |||||||
---|---|---|---|---|---|---|---|---|---|
Mechanistic Model | Two-Step Approach | Mechanistic Model | Two-Step Approach | Mechanistic Model | Two-Step Approach | ||||
μM | pmol/mg/min | μl/mg/min | |||||||
CCK8 | |||||||||
Rat hepatocytes | 20.1 ± 2.5 (12.4%) | 22.4 ± 12.0 (53.6%) | 421 ± 34 (8.1%) | 440 ± 121 (27.5%) | 0.805 ± 0.215 (26.7%) | 0.104 ± 0.453 (436%) | |||
CHO-Oatp1b2 | 13.9 ± 2.4 (17.3%) | 8.6 ± 5.8 (67.4%)# | 73.0 ± 9.9 (13.6%) | 78.9 ± 23.2 (29.4%) | 0.029 ± 0.054 (186%) | 0.007 ± 0.119 (1700%) | |||
CHO-OATP1B3 | 15.2 ± 2.2 (14.5%) | 22.1 ± 18.5 (83.7%) | 238 ± 25 (10.5%) | 278 ± 117 (42.1%) | 0.311 ± 0.128 (41.1%) | 0.076 ± 0.369 (486%) | |||
Deltorphin II | |||||||||
Rat hepatocytes | 150 ± 99 (66.0%) | 130 ± 167 (128%) | 190 ± 118 (62.0%) | 232 ± 318 (137%) | 0.210 ± 0.211 (100%) | 0 ± 0.400 | |||
CHO-Oatp1b2 | 118 ± 36 (30.5%) | 64.9 ± 80.7 (124%) | 82.6 ± 23.3 (28.2%) | 56.1 ± 39.2 (70.0%) | 0.030 ± 0.042 (139%) | 0.036 ± 0.051 (142%) | |||
Fexofenadine | |||||||||
Rat hepatocytes | 271 ± 35 (12.9%) | 27.2 ± 29.2 (107%) | 3162 ± 274 (8.7%) | 391 ± 146 (37.3%) | 2.08 ± 0.67 (31.7%) | 3.26 ± 0.26 (8.0%) | |||
CHO-Oatp1a1 | 51.0 ± 19.0 (37.3%) | 12.3 ± 37.9 (308%) | 580 ± 134 (23.0%) | 144 ± 110 (96.5%) | 6.40 ± 1.19 (18.7%) | 3.14 ± 0.24 (7.6%) | |||
Pitavastatina | |||||||||
Rat hepatocytes | 71.7 ± 6.9 (9.6%) | 62.7 ± 36.0 (57.4%) | 8419 ± 897 (10.6%) | 5876 ± 1728 (29.4%) | 0.909 ± 1.043 (115%) | 3.23 ± 2.30 (71.2%) | |||
Napsagatran | |||||||||
Rat hepatocytes | 88.4 ± 8.1 (9.2%) | 31.3 ± 32.3 (103%) | 384 ± 19 (5.0%) | 337 ± 180 (53.4%) | 0 | 0 | |||
Mean CV (%) | 23.3 | 115** | 18.9 | 58.1*** | 82.3 | 407 |
↵** , p < 0.01
↵*** , p < 0.001: statistically significant difference of the CV between the two approaches shown by Student's t test
↵# , p < 0.05: statistically significant difference between Km of CHO-Oatp1b2 and Km of rat hepatocytes shown by Student's t test
↵ a Mechanistic model estimated fraction bound to 0.21 ± 0.10 for pitavastatin (0 for the four other compounds)