Summary of in vitro hepatic uptake intrinsic clearance for 15 OATP substrates
| Compound | Uptake in human hepatocytes (µl/min per million cells)a | Uptake in monkey hepatocytes (µl/min per million cells)a | Mean Fold Differencec | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lot | CLu,int,uptakeb | CLu,int,passiveb | CLu,int,active | Lot | CLu,int,uptakeb | CLu,int,passiveb | CLu,int,active | CLu,int,passive | CLu,int,active | |
| Asunaprevir | PZA | 1283.1 (122.2) | 75.4 (20) | 1207.7 | PNC | 1432.0 (292.5) | 38.8 (13.3) | 1393.2 | 0.7 | 1.1 |
| XPM | 2448.1 (242.4) | 154.8 (40.7) | 2293.3 | UHK | 2224.5 (169.9) | 76.5 (42.5) | 2148.1 | |||
| YTW | 1460.3 (380.9) | 144.6 (79.4) | 1315.7 | VNV | 1776.7 (40.0) | 129.9 (36.4) | 1646.8 | |||
| Donor mean | 1730.5 | 124.9 | 1605.6 | Donor mean | 1811.1 | 81.7 | 1729.4 | |||
| Donor S.D. | 627.7 | 43.2 | 598.0 | Donor S.D. | 397.4 | 45.7 | 384.1 | |||
| Atorvastatin | PZA | 112.5 (27.2) | 11.6 (4.0) | 100.9 | PNC | 326.4 (81.5) | 8.2 (2.0) | 318.2 | 1.0 | 3.0 |
| XPM | 138.7 (12.3) | 7.3 (2.5) | 131.4 | UHK | 414.3 (68.5) | 7.0 (5.9) | 407.3 | |||
| YTW | 76.2 (8.3) | 5.4 (3.8) | 70.8 | VNV | 184.0 (16.1) | 8.7 (1.1) | 175.3 | |||
| Donor mean | 109.1 | 8.1 | 101.0 | Donor mean | 308.2 | 8.0 | 300.3 | |||
| Donor S.D. | 31.4 | 3.2 | 30.3 | Donor S.D. | 116.2 | 0.9 | 117.0 | |||
| Bosentan | PZA | 82.7 (10.8) | 3.8 (0.2) | 78.9 | PNC | 175.9 (20.6) | 4.5 (2.5) | 171.4 | 1.3 | 3.3 |
| XPM | 90.9 (12.3) | 2.7 (0.3) | 88.2 | UHK | 380.2 (46.2) | 5.0 (6.4) | 375.2 | |||
| YTW | 74.0 (18.5) | 5.4 (2.2) | 68.6 | VNV | 242.1 (27.8) | 6.7 (4.7) | 235.5 | |||
| Donor mean | 82.6 | 4.0 | 78.6 | Donor mean | 266.1 | 5.4 | 260.7 | |||
| Donor S.D. | 8.4 | 1.4 | 9.8 | Donor S.D. | 104.2 | 1.2 | 104.2 | |||
| Cerivastatin | PZA | 175.1 (20.2) | 9.4 (7.2) | 165.7 | PNC | 311.1 (1.0) | 9.1 (3.5) | 302.0 | 1.1 | 1.9 |
| XPM | 223.3 (79.3) | 10.1 (2.9) | 213.3 | UHK | 415.2 (32.8) | 9.6 (7.1) | 405.6 | |||
| YTW | 151.3 (4.3) | 5.0 (0.7) | 146.3 | VNV | 312.6 (68.7) | 9.1 (1.0) | 303.5 | |||
| Donor mean | 183.2 | 8.2 | 175.1 | Donor mean | 346.3 | 9.3 | 337.0 | |||
| Donor S.D. | 36.7 | 2.7 | 34.5 | Donor S.D. | 59.6 | 0.3 | 59.3 | |||
| Danoprevir | PZA | 98.1 (20.2) | 16.3 (7.4) | 81.8 | PNC | 169.2 (43.0) | 13.6 (2.2) | 155.6 | 0.7 | 2.3 |
| XPM | 167.6 (79.3) | 17.1 (5.4) | 150.5 | UHK | 355.5 (116.0) | 6.2 (5.2) | 349.3 | |||
| YTW | 95.4 (4.3) | 14.0 (0.7) | 81.5 | VNV | 224.4 (61.4) | 15.1 (21.5) | 209.3 | |||
| Donor mean | 120.4 | 15.8 | 104.6 | Donor mean | 249.7 | 11.6 | 238.1 | |||
| Donor S.D. | 40.9 | 1.6 | 39.8 | Donor S.D. | 95.7 | 4.8 | 100.0 | |||
| Fluvastatin | PZA | 335.1 (56.1) | 19.0 (4.8) | 316.1 | PNC | 258.2 (11.6) | 9.2 (3.5) | 249.0 | 0.6 | 1.0 |
| XPM | 263.4 (45.8) | 22.5 (8.6) | 240.9 | UHK | 265.7 (24.8) | 6.4 (1.7) | 259.4 | |||
| YTW | 205.5 (21.6) | 9.5 (2.6) | 196.0 | VNV | 259.4 (17.3) | 16.8 (2.3) | 242.6 | |||
| Donor mean | 268.0 | 17.0 | 251.0 | Donor mean | 261.1 | 10.8 | 250.3 | |||
| Donor S.D. | 64.9 | 6.7 | 60.6 | Donor S.D. | 4.0 | 5.4 | 8.5 | |||
| Grazoprevir | PZA | 663.7 (145.3) | 97.2 (25.7) | 566.5 | PNC | 1175.9 (190.3) | 26.0 (9.6) | 1149.9 | 0.5 | 1.4 |
| XPM | 774.3 (191.1) | 34.6 (10.1) | 739.7 | UHK | 1145.1 (488) | 36.3 (4.8) | 1108.8 | |||
| YTW | 733.0 (177.7) | 30.2 (14.5) | 702.8 | VNV | 521.6 (119.8) | 23.3 (2.7) | 498.3 | |||
| Donor mean | 723.6 | 54.0 | 669.6 | Donor mean | 947.5 | 28.5 | 919.0 | |||
| Donor S.D. | 55.9 | 37.5 | 91.2 | Donor S.D. | 369.2 | 6.9 | 364.9 | |||
| Maraviroc | PZA | 5.0 (1.1) | 0.8 (0.4) | 4.2 | PNC | 33.2 (3.0) | 0.7 (1.1) | 32.6 | 0.5 | 4.2 |
| XPM | 6.6 (1.8) | 0.8 (0.1) | 5.8 | UHK | 22.2 (2.9) | 0.4 (0.3) | 21.8 | |||
| YTW | 7.0 (1.2) | 1.1 (0.3) | 5.9 | VNV | 13.5 (1.2) | 0.4 (0.5) | 13.1 | |||
| Donor mean | 6.2 | 0.9 | 5.3 | Donor mean | 23.0 | 0.5 | 22.5 | |||
| Donor S.D. | 1.0 | 0.2 | 1.0 | Donor S.D. | 9.9 | 0.2 | 9.7 | |||
| Pitavastatin | PZA | 281.2 (2.0) | 16.8 (1.9) | 264.4 | PNC | 477.9 (62.2) | 5.1 (0.9) | 472.7 | 0.7 | 2.0 |
| XPM | 311.0 (37.2) | 13.0 (1.9) | 298.0 | UHK | 620.1 (103.9) | 8.5 (1.7) | 611.6 | |||
| YTW | 204.8 (15.5) | 11.2 (1.9) | 193.7 | VNV | 451.4 (4.3) | 16.2 (11.1) | 435.3 | |||
| Donor mean | 265.7 | 13.7 | 252.0 | Donor mean | 516.5 | 9.9 | 506.5 | |||
| Donor S.D. | 54.7 | 2.8 | 53.2 | Donor S.D. | 90.7 | 5.7 | 92.9 | |||
| Pravastatin | PZA | 3.1 (0.6) | 0.7 (0.7) | 2.4 | PNC | 10.6 (0.4) | 0.2 (0.01) | 10.4 | 0.9 | 3.2 |
| XPM | 3.4 (1.1) | 0.6 (0.04) | 2.9 | UHK | 8.2 (0.7) | 0.7 (0.1) | 7.4 | |||
| YTW | 2.7 (0.8) | 0.2 (0.2) | 2.5 | VNV | 6.9 (1.4) | 0.4 (0.1) | 6.6 | |||
| Donor mean | 3.1 | 0.5 | 2.6 | Donor mean | 8.6 | 0.5 | 8.1 | |||
| Donor S.D. | 0.4 | 0.2 | 0.2 | Donor S.D. | 1.9 | 0.3 | 2.0 | |||
| Repaglinide | PZA | 224.8 (69.4) | 28.1 (3.3) | 196.7 | PNC | 500.0 (78.9) | 12.1 (4.9) | 487.9 | 1.0 | 2.1 |
| XPM | 257.9 (111.6) | 10.7 (1.7) | 247.1 | UHK | 552.8 (230.6) | 14.0 (29.1) | 538.8 | |||
| YTW | 177.7 (67.8) | 10.7 (1.7) | 166.9 | VNV | 299.2 (169.9) | 21.8 (13.3) | 277.3 | |||
| Donor mean | 220.1 | 16.5 | 203.6 | Donor mean | 450.6 | 16.0 | 434.7 | |||
| Donor S.D. | 40.3 | 10.0 | 40.5 | Donor S.D. | 133.8 | 5.2 | 138.6 | |||
| Rosuvastatin | PZA | 12.8 (0.01) | 1.5 (1.3) | 11.3 | PNC | 34.7 (2.6) | 0.9 (0.03) | 33.8 | 1.1 | 2.7 |
| XPM | 20.1 (1.6) | 1.3 (0.1) | 18.7 | UHK | 51.6 (9.8) | 1.7 (0.3) | 49.9 | |||
| YTW | 15.2 (2.4) | 1.0 (0.6) | 14.1 | VNV | 38.9 (4.5) | 1.6 (0.7) | 37.4 | |||
| Donor mean | 16.0 | 1.3 | 14.7 | Donor mean | 41.7 | 1.4 | 40.3 | |||
| Donor S.D. | 3.7 | 0.2 | 3.7 | Donor S.D. | 8.8 | 0.5 | 8.4 | |||
| Sorafenib | PZA | 110,666.7 (3333.3) | 4666.7 (2667.7) | 106,000.0 | PNC | 279,500.0 (43,285.7) | 21,071.4 (13,642.9) | 258,428.6 | 2.2 | 1.1 |
| XPM | 167,666.7 (20,000.0) | 9000.0 (2000.0) | 158,666.7 | UHK | 175,428.6 (37,642.9) | 18,357.1 (8642.9) | 157,071.4 | |||
| YTW | 216,666.7 (14,666.7) | 10,000.0 (2000.0) | 206,666.7 | VNV | 107,142.9 (2357.1) | 13,642.9 (1928.6) | 93,500.0 | |||
| Donor mean | 165,000.0 | 7888.9 | 157,111.1 | Donor mean | 187,357.1 | 17,690.5 | 169,666.7 | |||
| Donor S.D. | 53,050.3 | 2835.0 | 50,351.4 | Donor S.D. | 86,795.5 | 3758.9 | 83,182.6 | |||
| Telmisartan | PZA | 1133.3 (99.3) | 58.1 (19.7) | 1075.1 | PNC | 1943.6 (46.4) | 105.7 (23.5) | 1837.9 | 1.9 | 1.8 |
| XPM | 1043.8 (300.5) | 53.7 (48.3) | 990.2 | UHK | 2416.3 (167.4) | 138.0 (24.1) | 2278.3 | |||
| YTW | 1292.5 (11.6) | 65.3 (9.8) | 1227.2 | VNV | 1935.4 (129.2) | 98.6 (81.0) | 1836.8 | |||
| Donor mean | 1156.5 | 59.0 | 1097.5 | Donor mean | 2098.5 | 114.1 | 1984.3 | |||
| Donor S.D. | 125.9 | 5.9 | 120.1 | Donor S.D. | 275.3 | 21.0 | 254.6 | |||
| Valsartan | PZA | 84.7 (15.9) | 21.2 (4.2) | 63.5 | PNC | 221.1 (21.1) | 4.9 (4.0) | 216.3 | 0.4 | 3.3 |
| XPM | 105.8 (5.3) | 26.5 (5.3) | 79.4 | UHK | 252.0 (8.1) | 8.1 (2.1) | 243.9 | |||
| YTW | 58.2 (10.6) | 15.9 (0.5) | 42.3 | VNV | 154.5 (58.5) | 11.4 (11.3) | 143.1 | |||
| Donor mean | 82.9 | 21.2 | 61.7 | Donor mean | 209.2 | 8.1 | 201.1 | |||
| Donor S.D. | 23.9 | 5.3 | 18.6 | Donor S.D. | 49.9 | 3.3 | 52.1 | |||
| Mean | 1.0 | 2.3 | ||||||||
↵a The in vitro uptake clearance was assessed in three donors of human (lots PZA, XPM, and YTW) and monkey (lots PNC, UHK, and VNV) hepatocytes. The initial uptake rates were estimated from the slopes of linear uptake phase using linear regression fitting. The intrinsic uptake clearance values were calculated by dividing the initial uptake velocity by the nominal substrate concentration. For each donor, the experiments were conducted in triplicates for each time point. The mean values were averaged from the triplicates, and the S.D. are presented in parentheses. Additionally, the donor mean value and the donor S.D. value for each compound were obtained from the three donors using the mean value of each donor. 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.
↵b 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.
↵c Fold difference = mean value of data from three monkey hepatocyte lots/mean value of data from three human hepatocyte lots.