TABLE 2

Inhibition of Pgp-mediated transport of probe substrates across MDR1-MDCKII cells

The inhibition of probe substrates by test compounds was determined as described under Materials and Methods. A minimum of eight concentrations (n = 3) per test compound were used to determine the IC50 value (calcein-AM, digoxin, vinblastine, and colchicine) using the full four-parameter equation or K value (prazosin) using the Hill equation.


Inhibitor

EACa

Category

Calcein-AM IC50 Valueb

Digoxin B→A IC50 Value

Vinblastine B→A IC50 Value

Colchicine B→A IC50 Value

Prazosin A→B K Valuec

Prazosin B→A IC50 Value
GF120918 NNY I Inhibitor 0.101 ± 0.014 0.055 ± 0.003 0.043 ± 0.004 0.027 ± 0.002 0.050 ± 0.027 0.025 ± 0.003
Ranitidine NNN I Unambiguous nonsubstrates No No No No No
Propranalol NNN No No No No >100e
Methotrexate NNN No No No No No
Triamterene NNN No No No No No
Amprenavir YYY I Unambiguous substrates >100 No >100 91.3 ± 11.6 >100
Prazosind YYY >100e Nod Nod 70.7 ± 3.8 Nod
Quinidine YYY 55.5 ± 2.34 14.9 ± 9.0 22.9 ± 3.4 51.7 ± 9.8 14.0 ± 1.23
Vinblastine YYY >100 17.8 ± 2.2 89.7 ± 15.6 30.1 ± 4.1 21.9 ± 11.7
Verapamil NYY IIA Nontransported substrates 60.9 ± 8.91 10.7 ± 4.1 33.5 ± 2.1 17.3 ± 1.9 1.18 ± 0.20 1.55 ± 0.56
Diphenhydramine NYY No No No No Nod
Ketoconazole NYY 10.1 ± 1.6 3.07 ± 0.76 6.34 ± 1.98 5.49 ± 0.98 2.38 ± 0.18 0.65 ± 0.12
Daunorubicin YNN No No >100 >100 No
Colchicine YNN IIB1 Transported substrates No No No No No
Dexamethasone YNN No No No No No
Fexofenadine Y-N No No No No No
Digoxin Y-N No No No No No
Erythromycin YYN IIB2 Transported substrates No No No No No
Indinavir YYN No No No No >50
Trimethoprim YYN No No No No No
Cyclosporin A
YNY
IIB3 Transported substrates
2.22 ± 0.02
1.6 ± 0.3
6.18 ± 1.90
1.36 ± 0.09
0.98 ± 0.33
0.74 ± 0.12
  • a EAC: E, monolayer efflux; A, drug-stimulated ATPase; C, calcein-AM. Results are reported as yes (Y) or no (N). For efflux, yes = substrate and no = nonsubstrate; for ATPase assay, yes = stimulator and no = no activity; and for calcein-AM assay, yes = response >10% maximum fluorescence and no = response <10% maximum fluorescence. See Polli et al. (2001) for further details.

  • b IC50 is the concentration of inhibitor required for 50% inhibition of probe transport.

  • c K value is the concentration of inhibitor required for 50% increase in the prazosin A→B rate.

  • d Prazosin >50 μM increased LY passive permeability (>20 nm/s), suggesting a breach in the tight junctions between monolayers; therefore, data only up to 50 μM were used in the analysis of IC50 curves.

  • e Compounds with an IC50 value reported to be greater than a number representing that notable inhibition (>20%) was observed at the highest test concentration. However, an accurate IC50 value could not be determine from the dataset.