In vitro transport activity of 16 large lipophilic acids in the OATP1B1-transfected HEK293 cells and monkey and human primary hepatocytes
| Compound | OATP1B1 Uptake Ratioa [Mean (%CV)] | OATP1B1 Inhibitionb (Mean) | Human PSinfc [Mean (%CV)] | Human PSinf,+Rifc [Mean (%CV)] | Monkey PSinfc [Mean (%CV)] | Monkey PSinf,+Rifc [Mean (%CV)] | fu,hepsd [Mean (%CV)] | Human In Vitro ft,OATP1B (Mean) | Monkey In Vitro ft,OATP1B (Mean) | Monkey In Vivo ft,OATP1B (Mean) |
|---|---|---|---|---|---|---|---|---|---|---|
| % inhibition at 10 µM | ml/min per kilogram | ml/min per kilogram | ml/min per kilogram | ml/min per kilogram | ||||||
| Danoprevir | 9.6 (6)* | 98 | 151.2 (7) | 70.6 (9)* | 70.6 (11) | 48.9 (11)* | 0.30 (9) | 0.53 | 0.31 | 0.34 |
| Dexloxiglumide | 2.0 (6)* | 82 | 21.7 (27) | 7.6 (22)* | 13.1 (23) | 4.0 (14)* | 0.73 (22) | 0.65 | 0.69 | 0.68 |
| Epristeride | 0.8 (4) | 52 | 141.6 (9) | 115.4 (17) | 75.1 (11) | 71.8 (15) | 0.48 (9) | 0.19 | 0.04 | 0.03 |
| Gliquidone | 1.0 (2) | 99 | 78.9 (26) | 137.1 (31) | 61.5 (20) | 102.6 (23) | 0.51 (4) | 0 | 0 | 0.82 |
| Glyburide | 2.2 (6)* | 95 | 91.5 (13) | 37.0 (27)* | 126.3 (8) | 54.2 (11)* | 0.51 (17) | 0.60 | 0.57 | 0.92 |
| GSK269984A | 0.8 (2) | 100 | 70.5 (14) | 88.2 (13) | 133.8 (19) | 134.6 (24) | 0.21 (5) | 0 | 0 | 0.56 |
| Irbesartan | 3.1 (4)* | 79 | 75.6 (10) | 16.6 (20)* | 302.4 (18) | 70.6 (16)* | 0.67 (5) | 0.78 | 0.77 | 0.69 |
| LY2393910 | 0.9 (11) | 42 | 12.6 (18) | 9.6 (37) | 6.6 (33) | 4.5 (43) | 0.00024 (14) | 0.24 | 0.31 | 0.54 |
| LY2409021 | 1.1 (12) | 54 | 32.8 (17) | 100.8 (16) | 58.0 (36) | 118.4 (26) | 0.00078 (15) | 0 | 0 | 0.60 |
| MK-0893 | 1.1 (7) | 61 | 40.3 (26) | 75.6 (21) | 18.9 (31) | 32.8 (37) | 0.00058 (17) | 0 | 0 | 0.84 |
| MK-3577 | 3.1 (4)* | 83 | 113.4 (10) | 40.3 (16)* | 158.8 (10) | 30.2 (23)* | 0.0037 (17) | 0.64 | 0.81 | 0.96 |
| Montelukast | 1.0 (3) | 99 | 163.8 (52) | 186.5 (36) | 55.4 (31) | 141.1 (38) | 0.0037 (13) | 0 | 0 | 0.49 |
| PF-05089771 | 1.6 (4)* | 95 | 78.1 (29) | 37.8 (24)* | 128.0 (10) | 59.5 (6)* | 0.36 (12) | 0.52 | 0.54 | 0.69 |
| PF-05241328 | 2.2 (2)* | 86 | 131.0 (27) | 68.5 (13)* | 75.6 (9) | 32.8 (16)* | 0.21 (8) | 0.48 | 0.57 | 0.76 |
| Pitavastatin | 9.9 (2)* | 96 | 425.9 (12) | 214.2 (15)* | 473.8 (18) | 196.6 (15)* | 0.67 (16) | 0.50 | 0.59 | 0.80 |
| Verlukast | 1.5 (7)* | 98 | 219.2 (8) | 148.7 (8)* | 244.4 (6) | 115.9 (18)* | 0.20 (14) | 0.32 | 0.53 | 0.92 |
↵a Ratio of cell accumulation in HEK-OATP1B1 cells to HEK–wild-type cells (n = 6). *P < 0.05, uptake significantly higher in transfect cells compared with wild-type cells (unpaired t test).
↵b Inhibition of OATP1B1-mediated uptake of rosuvastatin in transfected HEK cells. Value represent mean percent inhibition at 10 µM conc. (n = 3). Variability in the inhibition studies was within 10% coefficient of variance (not shown).
↵c Apparent uptake clearance measured in human or monkey hepatocytes in the absence (PSinf) and presence (PSinf,+Rif) of 100 µM rifampicin. Values represent mean and percent coefficient of variance estimated from two to four independent experiments, each experiment run in triplicate. *P < 0.05, uptake significantly inhibited by rifampicin (unpaired t test).
↵d fu,heps was measured by equilibrium dialysis using human hepatocytes (see Materials and Methods).