Table 2. Inhibition of the transport of model substrates by transporters identified to transport creatinine by drugs that reduce the active tubular secretion of creatinine.
| IC50 (μmol/l) | |||||
|---|---|---|---|---|---|
| |
OAT2 |
OCT2 |
OCT3 |
MATE1 |
MATE2-K |
| Cimetidine | 72.8±17.0 | 135±16 | 87.7±55.1 | 1.46±0.11 | 46.6±7.23 |
| Trimethoprim | >300 | 68.0±5.2 | 12.3±5.2 | 3.31±0.67 | 1.87±0.57 |
| Cobicistat | >100 | 24.0±4.6 | >100 | 1.87±0.22 | 33.5±4.2 |
| Ritonavir | >20 | ∼20 | >20 | 1.34±0.23 | >20 |
| Dolutegravir | >100 | 0.066±0.003 | >100 | 4.67±1.11 | >100 |
Abbreviations: IC50, half-maximal inhibitory concentration; MATE1 and MATE2-K, multidrug and toxin extrusion transporters 1 and 2-K; OAT2, organic anion transporter 2; OCT2 and OCT3, organic cation transporters 2 and 3.
Inhibition constants were measured for OAT2 transport of 3′, 5′-cyclic GMP, OCT3 transport of 1-methyl-4-phenylpyridinium, and OCT2, MATE1, and MATE-2K transport of tetraethylammonium.
Inhibition by compounds was studied by threefold serial dilution up to 20 μmol/l (ritonavir), 100 μmol/l (cobicistat and dolutegravir), and 300 μmol/l (cimetidine and trimethoprim). The highest concentrations tested were based on aqueous solubility limits.
IC50 values represent the average plus/minus s.e.m. from curve fitting of at least two measurements per inhibitor concentration.