PTIP values and cellular uptake parameters of selected transporter/inhibitor pairs
For comparability across PTIP-positive and PTIP-negative transporter/inhibitor combinations, “NSB block −” PTIP values are shown in each case. When determined in the presence of a specific and potent inhibitor, Kp reflects passive equilibration. Kp,uu values >1 indicate active accumulation. For calculations see Materials and Methods.
| Transporter | Inhibitor | PTIP | Cellular Uptake Parameters | |||||
|---|---|---|---|---|---|---|---|---|
| Time to Steady State | PSinfa | Kp w/o Inhibitor: Passive and Active | Kp with Inhibitor: Passive Only | fu,cell | Kp,uu | |||
| Fold | min | μl/min per 106 cells | ||||||
| OCT1 | Ledipasvir | >594 | >180b | 0.171 | 155 | 123 | 0.00816 | 1.27 |
| OATP1B1 | Venetoclax | 203 | >180b | 0.92 | 266 | 263 | 0.0038 | 1.01 |
| OATP1B1 | Cyclosporin A | 5.88 | 120 | 0.92 | 310 | 259 | 0.00387 | 1.20 |
| OATP1B1 | Saquinavir | 3.17 | 60 | 10.4 | 729 | 416 | 0.00256 | 1.75 |
| OAT3 | Benzbromarone | 4.96 | 60 | 8.29 | 333 | 333 | 0.003 | 1.00 |
| OAT1 | Benzbromarone | 1.82 | 15 | 11.1 | 486 | 396 | 0.00253 | 1.23 |
| OAT3 | Valsartan | 1.40 | 3 | 5.59 | 17.8 | 1.33 | 0.752 | 13.3 |
| OCT2 | Trimethoprim | 1.28 | 1 | 9.2 | 13.3 | 4.85 | 0.151 | 2.73 |
fu,cell, unbound fraction in the cell; Kp, ratio of steady-state total concentrations measured in the cells versus medium; Kp,uu, ratio of steady-state unbound concentrations in the cells versus medium; PSinf, cellular uptake clearance normalized to cell number.
↵a Time points used for the calculation of the initial slope: ledipasvir: 1–30 min; venetoclax: 1–90 min; cyclosporine A: 15–120 min; saquinavir: 1–5 min; benzbromarone (OAT1 and OAT3): 1–5 min; valsartan: 0 to 1 min; trimethoprim: 0 to 1 min.
↵b Kp values of ledipasvir and venetoclax were calculated with an approximation assuming steady state was reached at 180 min.