Pharmacokinetic parameters
| Parameter | Wild Type | oatp1a/1b KO | OATP1B1 KI | OATP1B3 KI |
|---|---|---|---|---|
| Carboxydichlorofluorescein (10 mg/kg i.v.; mean ± S.D., n = 10) | ||||
| AUC (μg·h/ml)a | 22.2 ± 17.6 | 57.0 ± 64.0* | 35.8 ± 24.7 | 21.8 ± 6.9 |
| CLblood (ml/min/kg) | 10.1 ± 4.0 | 5.8 ± 3.6* | 5.8 ± 2.0* | 8.2 ± 2.1 |
| VD,SS (ml/kg) | 583 ± 419 | 264 ± 144 | 237 ± 97 | 327 ± 78 |
| Pravastatin (10 mg/kg i.v.; mean ± S.D., n = 4) | ||||
| AUC (μg·h/ml) | 13.7 ± 9.6 | 58.8 ± 92.8 | 12.8 ± 1.8 | 50.0 ± 56.5 |
| CLblood (ml/min/kg) | 15.8 ± 7.4 | 10.6 ± 7.0 | 13.2 ± 1.8 | 8.1 ± 6.8 |
| VD,SS (ml/kg) | 265 ± 101 | 210 ± 96 | 227 ± 100 | 182 ± 75 |
| Pravastatin (100 mg/kg p.o.; mean ± S.D., n = 4) | ||||
| AUC (μg·h/ml) | 0.21 ± 0.04 | 24.1 ± 4.8* | 16.6 ± 1.4* | 15.3 ± 2.7* |
| Cmax (ng/ml) | 91 ± 34 | 19,400 ± 9530* | 11,600 ± 8240* | 10,300 ± 6170* |
| Tmax (h) | 1.8 ± 2.8 | 0.6 ± 0.3 | 0.6 ± 0.3 | 0.6 ± 0.3 |
| F (%) | 0.2 ± 0.1 | 14.7 ± 10.9* | 13.2 ± 2.5* | 7.6 ± 6.1* |
| Atorvastatin (10 mg/kg i.v.; mean ± S.D., n = 6) | ||||
| AUC (μg·h/ml) | 5.2 ± 3.4 | 89.1 ± 161.1* | 16.7 ± 28.5 | 7.9 ± 4.2 |
| CLblood (ml/min/kg) | 48 ± 32 | 12 ± 10* | 29 ± 16 | 27 ± 13 |
| VD,SS (ml/kg) | 816 ± 285 | 323 ± 199* | 475 ± 219 | 404 ± 162 |
| Atorvastatin (300 mg/kg p.o.; mean ± S.D., n = 5–6) | ||||
| AUC (μg·h/ml) | 4.9 ± 8.2 | 14.4 ± 6.4* | 10.4 ± 4.4* | 96.4 ± 5.9* |
| Cmax (ng/ml) | 2160 ± 3110 | 8778 ± 4763* | 6762 ± 3140* | 6407 ± 3973* |
| Tmax (h) | 3.0 ± 2.3 | 0.6 ± 0.3* | 0.8 ± 0.3* | 1.5 ± 2.2 |
| F (%) | 3.2 ± 3.4 | 2.1 ± 2.0 | 6.8 ± 3.4 | 4.5 ± 3.3 |
| Simvastatin (10 mg/kg i.v.; composite PK mean, n = 5–6 mice per time point) | ||||
| Lactone AUC (μg·h/ml) | 2.04 | 3.32 | 3.86 | 2.43 |
| Acid AUC (μg·h/ml) | 1.55 | 2.87 | 3.91 | 2.04 |
| Lactone CL (ml/min/kg) | 81.7 | 50.2 | 43.2 | 68.6 |
| Total CL (ml/min/kg)b | 47.3 | 27.5 | 21.9 | 38.0 |
| VD,SS (ml/kg) | 13,900 | 11,900 | 12,500 | 12,500 |
| Simvastatin (100 mg/kg p.o.; composite PK mean, n = 5–6 mice per time point) | ||||
| Lactone AUC (μg·h/ml) | 3.87 | 8.24 | 2.85 | 4.32 |
| Acid AUC (μg·h/ml) | 3.17 | 10.3 | 2.58 | 11.4 |
| Lactone Cmax (ng/ml) | 1640 | 1610 | 517 | 767 |
| Acid Cmax (ng/ml) | 1360 | 1270 | 430 | 679 |
| Lactone Tmax (h) | 1.0 | 1.0 | 1.0 | 1.5 |
| Acid Tmax (h) | 1.0 | 1.0 | 1.0 | 1.5 |
| Lactone F (%) | 19.0 | 24.8 | 7.4 | 17.8 |
| Total F (%)b | 19.6 | 29.8 | 7.0 | 34.8 |
CL, clearance; CLblood, blood clearance; F, bioavailability; Tmax, time of Cmax; VD,SS, volume of distribution.
↵a AUC values for carboxydichlorofluorescein and simvastatin are extrapolated to infinity; AUC values for pravastatin and atorvastatin are reported through the last time point due to inability to estimate terminal slope in some animal groups (see Figs. 2 and 3).
↵b Total simvastatin is the sum of lactone and acid normalized for molecular weight difference
↵* P < 0.05, knockout or knockin versus wild-type mice.