Prediction of OATP1B1-mediated DDIs with a static model
The R values of CsA, rifampin, and gemfibrozil were determined using Ki values obtained from each probe substrate and [I] (Cmax or [I]u,inlet,max) based on eqs. 5 and 6. The Ki values were taken from Table 2. Cmax and [I]u,inlet,max of the inhibitors are given in Supplemental Table 1.
| Substrates | Inhibitors | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CsA | Rifampin | Gemfibrozil | ||||||||||
| Ki | R Value (= 1+[I]/Ki)a | Observed AUCRa | Ki | R Value (= 1+[I]/Ki)b | Observed AUCRb | Ki | R Value (= 1+[I]/Ki)c | Observed AUCRc | ||||
| [I] = Cmax | [I] = [I]u,inlet,max | [I] = Cmax | [I] = [I]u,inlet,max | [I] = Cmax | [I] = [I]u,inlet,max | |||||||
| µM | µM | µM | ||||||||||
| In vitro prototypical probe substrates | ||||||||||||
| E2G | 0.118 | 9.05 (4.05–13.7) | 11.2 (4.81–17.1) | NA | 0.585 | 40.3 | 18.1 | NA | 26.4 | 4.79 | 1.09 | NA |
| E1S | 0.732 | 2.30 (1.49–3.05) | 2.64 (1.61–3.60) | NA | 6.96 | 4.30 | 2.44 | NA | 381 | 1.26 | 1.01 | NA |
| BSP | 0.694 | 2.37 (1.52–3.16) | 2.73 (1.65–3.74) | NA | 2.75 | 9.36 | 4.64 | NA | 173 | 1.58 | 1.01 | NA |
| Clinically used substrate drugs | ||||||||||||
| Pitavastatin | 0.228 | 5.17 (2.58–7.58) | 6.26 (2.97–9.33) | 4.6d | 1.07 | 22.5 | 10.3 | 5.7g | 58.5 | 2.70 | 1.04 | 1.5d |
| Atorvastatin | 0.160 | 6.94 (3.25–10.4) | 8.50 (3.81–12.9) | 9.0d, 15d | 0.922 | 25.9 | 11.8 | 7.3d,j, 8.5d, 12d | 46.0 | 3.17 | 1.05 | 1.3d |
| Fluvastatin | 0.157 | 7.05 (3.29–10.6) | 8.64 (3.87–13.1) | 3.5d | 1.05 | 22.9 | 10.5 | NR | 72.7 | 2.38 | 1.03 | 1.1d |
| Rosuvastatin | 0.301 | 4.16 (2.20–5.98) | 4.99 (2.50–7.31) | 7.1e | 0.952 | 25.2 | 11.5 | 4.4g | 63.6 | 2.57 | 1.04 | 1.9d |
| Pravastatin | 0.184 | 6.16 (2.96–9.15) | 7.52 (3.45–11.3) | 12d, 23d | 0.653 | 36.2 | 16.3 | 2.6d, 4.6d | 9.65 | 11.4 | 1.26 | 2.0d |
| Repaglinide | 0.0857 | 12.1 (5.20–18.5) | 15.0 (6.25–23.2) | 2.4d | 0.598 | 39.5 | 17.7 | NR | 48.3 | 3.07 | 1.05 | 7.0d, 7.6d, 8.1d, 8.2d |
| Nateglinide | 0.244 | 4.89 (2.48–7.15) | 5.92 (2.84–8.79) | NR | 0.358 | 65.2 | 28.9 | NR | 252 | 1.40 | 1.01 | 1.5d |
| Glibenclamide | 0.102 | 10.3 (4.53–15.7) | 12.8 (5.41–19.6) | NR | 0.442 | 53.0 | 23.6 | 2.2d,j | 29.6 | 4.38 | 1.08 | NR |
| Bosentan | 0.206 | 5.61 (2.75–8.28) | 6.83 (3.18–10.2) | 2.0f | 0.694 | 34.1 | 15.4 | 5h,k | 36.6 | 3.73 | 1.07 | NR |
| Valsartan | 0.138 | 7.88 (3.61–11.9) | 9.70 (4.26–14.8) | NR | 0.377 | 62.0 | 27.5 | NR | 13.4 | 8.46 | 1.19 | NR |
| Torasemide | 0.486 | 2.95 (1.74–4.09) | 3.47 (1.93–4.91) | NR | 1.23 | 19.7 | 9.13 | NR | 49.5 | 3.02 | 1.05 | NR |
| Fexofenadine | 0.0771 | 13.3 (5.67–20.5) | 16.6 (6.84–25.6) | NR | 0.423 | 55.4 | 24.6 | 3.9–4.6i | 31.4 | 4.18 | 1.08 | NR |
NA, not applicable; NR, not reported.
↵a Dose of CsA ranged from 75 to 322 mg in clinical DDI studies. The R value is presented as the representative value that was calculated based on a 200-mg dose of CsA with the range in parenthesis. The R value range that corresponds to the clinical dose range (75–322 mg) was calculated based on the parameters of CsA given in Supplemental Table 1 assuming the linear pharmacokinetics.
↵b Dose of rifampin was 600 mg in clinical DDI studies and R value calculation.
↵c Dose of gemfibrozil was 600 mg in clinical DDI studies and R value calculation.
↵d Yoshida et al., 2012.
↵e Simonson et al., 2004.
↵f Binet et al., 2000.
↵g Prueksaritanont et al., 2014.
↵h van Giersbergen et al., 2007.
↵i Kusuhara et al., 2013.
↵j The inhibitor was given as a single intravenous dose.
↵k Fold increase in the trough concentration on day 2.