Derivation of a System-Independent for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC Data.

It has been previously demonstrated that IC values for inhibition of digoxin transport across confluent polarized cell monolayers are system-dependent. Digoxin IC data from five laboratories participating in the P-glycoprotein (P-gp) IC Initiative, using Caco-2, MDCKII-hMDR1 or LLC-PK1-hMDR1 cells, were fitted by the structural mass action kinetic model for P-gp-mediated transport across confluent cell monolayers. We determined their efflux-active P-gp concentration [T(0)], inhibitor elementary dissociation rate constant from P-gp (), digoxin basolateral uptake clearance (), and inhibitor binding affinity to the digoxin basolateral uptake transporter ().