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.

KiR Value (= 1+[I]/Ki)aObserved AUCRaKiR Value (= 1+[I]/Ki)bObserved AUCRbKiR Value (= 1+[I]/Ki)cObserved AUCRc
[I] = Cmax[I] = [I]u,inlet,max[I] = Cmax[I] = [I]u,inlet,max[I] = Cmax[I] = [I]u,inlet,max
In vitro prototypical probe substrates
 E2G0.1189.05 (4.05–13.7)11.2 (4.81–17.1)NA0.58540.318.1NA26.44.791.09NA
 E1S0.7322.30 (1.49–3.05)2.64 (1.61–3.60)NA6.964.302.44NA3811.261.01NA
 BSP0.6942.37 (1.52–3.16)2.73 (1.65–3.74)NA2.759.364.64NA1731.581.01NA
Clinically used substrate drugs
 Pitavastatin0.2285.17 (2.58–7.58)6.26 (2.97–9.33)4.6d1.0722.510.35.7g58.52.701.041.5d
 Atorvastatin0.1606.94 (3.25–10.4)8.50 (3.81–12.9)9.0d, 15d0.92225.911.87.3d,j, 8.5d, 12d46.
 Fluvastatin0.1577.05 (3.29–10.6)8.64 (3.87–13.1)3.5d1.0522.910.5NR72.72.381.031.1d
 Rosuvastatin0.3014.16 (2.20–5.98)4.99 (2.50–7.31)7.1e0.95225.211.54.4g63.62.571.041.9d
 Pravastatin0.1846.16 (2.96–9.15)7.52 (3.45–11.3)12d, 23d0.65336.216.32.6d, 4.6d9.6511.41.262.0d
 Repaglinide0.085712.1 (5.20–18.5)15.0 (6.25–23.2)2.4d0.59839.517.7NR48., 7.6d, 8.1d, 8.2d
 Nateglinide0.2444.89 (2.48–7.15)5.92 (2.84–8.79)NR0.35865.228.9NR2521.401.011.5d
 Glibenclamide0.10210.3 (4.53–15.7)12.8 (5.41–19.6)NR0.44253.023.62.2d,j29.64.381.08NR
 Bosentan0.2065.61 (2.75–8.28)6.83 (3.18–10.2)2.0f0.69434.115.45h,k36.63.731.07NR
 Valsartan0.1387.88 (3.61–11.9)9.70 (4.26–14.8)NR0.37762.027.5NR13.48.461.19NR
 Torasemide0.4862.95 (1.74–4.09)3.47 (1.93–4.91)NR1.2319.79.13NR49.53.021.05NR
 Fexofenadine0.077113.3 (5.67–20.5)16.6 (6.84–25.6)NR0.42355.424.63.9–4.6i31.44.181.08NR
  • 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.