Summary of in vitro hepatic intrinsic clearance in buffer with and without serum
| Serum free buffer | Buffer with 10% serum | Fold differenceb | ||||||
|---|---|---|---|---|---|---|---|---|
| CLu,int,uptakea | CLu,int,passivea | CLu,int,activea | CLu,int,uptakea | CLu,int,passivea | CLu,int,activea | CLu,int,passive | CLu,int,active | |
| Human hepatic uptake: lot XPM | ||||||||
| Asunaprevir | 119.7 (52.3) | 19.4 (2.9) | 100.3 | 2448.1 (242.4) | 154.8 (40.7) | 2293.3 | 8.0 | 22.9 |
| Atorvastatin | 47.9 (2.0) | 5 (1.9) | 42.9 | 138.7 (12.3) | 7.3 (2.5) | 131.4 | 1.5 | 3.1 |
| Bosentan | 28.5 (12.8) | 4.9 (1.2) | 23.6 | 90.9 (12.3) | 2.7 (0.3) | 88.2 | 0.6 | 3.7 |
| Cerivastatin | 57.4 (16.1) | 5.3 (0.1) | 52.1 | 223.3 (79.3) | 10.1 (2.9) | 213.3 | 1.9 | 4.1 |
| Danoprevir | 43 (8.5) | 6.2 (2.0) | 36.8 | 167.6 (79.3) | 17.1 (5.4) | 150.5 | 2.8 | 4.1 |
| Fluvastatin | 58.7 (36.8) | 4.8 (2.9) | 53.9 | 263.4 (45.8) | 22.5 (8.6) | 240.9 | 4.7 | 4.5 |
| Grazoprevir | 94.6 (28.6) | 12.4 (2.9) | 82.2 | 774.3 (191.1) | 34.6 (10.1) | 739.7 | 2.8 | 9.0 |
| Maraviroc | 4.4 (0.08) | 0.6 (0.3) | 3.8 | 6.6 (1.8) | 0.8 (0.1) | 5.8 | 1.3 | 1.5 |
| Pitavastatin | 50.1 (2.6) | 5 (1.2) | 45.1 | 311.0 (37.2) | 13.0 (1.9) | 298.0 | 2.6 | 6.6 |
| Pravastatin | 2.3 (0.7) | 0.6 (0.2) | 1.7 | 3.4 (1.1) | 0.6 (0.04) | 2.9 | 1.0 | 1.7 |
| Repaglinide | 62.3 (18.2) | 14.3 (3.9) | 48 | 257.9 (111.6) | 10.7 (1.7) | 247.1 | 0.8 | 5.1 |
| Rosuvastatin | 13.5 (2.2) | 1.4 (0.7) | 12.1 | 20.1 (1.6) | 1.3 (0.1) | 18.7 | 1.0 | 1.5 |
| Sorafenib | 215.9 (67.1) | 44.3 (20.6) | 171.6 | 167,666.7 (20,000.0) | 9000.0 (2000.0) | 158,666.7 | 203.2 | 924.6 |
| Telmisartan | 156.2 (15.7) | 26.8 (5.6) | 129.4 | 1043.8 (300.5) | 53.7 (48.3) | 990.2 | 2.0 | 7.7 |
| Valsartan | 7.5 (1.2) | 2.3 (0.9) | 5.2 | 105.8 (5.3) | 26.5 (5.3) | 79.4 | 11.5 | 15.3 |
| Monkey hepatic uptake: lot UHK | ||||||||
| Asunaprevir | 205.7 (46.9) | 20.7 (4.2) | 185 | 2224.5 (169.9) | 76.5 (42.5) | 2148.1 | 3.69 | 11.61 |
| Atorvastatin | 119.7 (10.7) | 5.7 (4.2) | 114 | 414.3 (68.5) | 7.0 (5.9) | 407.3 | 1.24 | 3.57 |
| Bosentan | 56 (6.4) | 3 (0.8) | 53 | 380.2 (46.2) | 5.0 (6.4) | 375.2 | 1.67 | 7.08 |
| Cerivastatin | 77.3 (12.9) | 4.3 (3.2) | 73 | 415.2 (32.8) | 9.6 (7.1) | 405.6 | 2.23 | 5.56 |
| Danoprevir | 99.7 (22.3) | 5.4 (0.9) | 94.3 | 355.5 (116.0) | 6.2 (5.2) | 349.3 | 1.15 | 3.70 |
| Fluvastatin | 88 (15.5) | 5.4 (1.9) | 82.6 | 265.7 (24.8) | 6.4 (1.7) | 259.4 | 1.18 | 3.14 |
| Grazoprevir | 156.4 (33.1) | 19.8 (2.8) | 136.6 | 1145.1 (488) | 36.3 (4.8) | 1108.8 | 1.83 | 8.12 |
| Maraviroc | 18 (2.0) | 0.5 (0.4) | 17.5 | 22.2 (2.9) | 0.4 (0.3) | 21.8 | 0.79 | 1.25 |
| Pitavastatin | 125.4 (17.5) | 3.2 (2.3) | 122.2 | 620.1 (103.9) | 8.5 (1.7) | 611.6 | 2.66 | 5.00 |
| Pravastatin | 7.8 (0.6) | 0.5 (0.2) | 7.3 | 8.2 (0.7) | 0.7 (0.1) | 7.4 | 1.48 | 1.02 |
| Repaglinide | 251.8 (37.5) | 14.9 (2.3) | 236.9 | 552.8 (230.6) | 14.0 (29.1) | 538.8 | 0.94 | 2.27 |
| Rosuvastatin | 33.8 (3.7) | 1.2 (0.6) | 32.6 | 51.6 (9.8) | 1.7 (0.3) | 49.9 | 1.42 | 1.53 |
| Sorafenib | 241 (66.4) | 62.2 (47.9) | 178.8 | 175,428.6 (37,642.9) | 18,357.1 (8642.9) | 157,071.4 | 295.13 | 878.48 |
| Telmisartan | 313.8 (69.8) | 44.1 (15.2) | 269.7 | 2416.3 (167.4) | 138.0 (24.1) | 2278.3 | 3.13 | 8.45 |
| Valsartan | 21.6 (1.9) | 1.9 (0.3) | 19.7 | 252.0 (8.1) | 8.1 (2.1) | 243.9 | 4.28 | 12.38 |
↵a The in vitro uptake clearance was assessed in single donor of human (lot XPM) and monkey (lot UHK) hepatocytes. The initial uptake rates were estimated from the slopes of linear uptake phase using linear regression fitting. The experiments were conducted in triplicates for each time point. The mean values were averaged from the triplicates, and the S.D.s are presented in parentheses. The intrinsic uptake clearance values were calculated by dividing the initial uptake velocity by the nominal substrate concentration. The CLint,active was calculated by subtracting the CLint,passive from CLint,uptake. In vitro uptake clearance is reported as microliters per minute per million cells. In vitro uptake clearance measured in uptake buffer containing 10% human or monkey serum was obtained by normalizing the free fraction of protein binding in 10% serum buffer.
↵b Fold difference = CLu,int in 10% serum buffer/CLu,int in serum free buffer.