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Derivation of a System-Independent K i for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC 50 Data

Drug Metabolism and Disposition, ISSN: 0090-9556, Vol: 46, Issue: 3, Page: 279-290
2018
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It has been previously demonstrated that IC 50 values for inhibition of digoxin transport across confluent polarized cell monolayers are system-dependent. Digoxin IC 50 data from five laboratories participating in the P-glycoprotein (P-gp) IC 50 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 ( k rQ ), digoxin basolateral uptake clearance ( k B ), and inhibitor binding affinity to the digoxin basolateral uptake transporter ( K QB ). We also fitted the IC 50 data for inhibition of digoxin transport through monolayers of primary human proximal tubule cells (HPTCs). All cell systems kinetically required a basolateral uptake transporter for digoxin, which also bound to all inhibitors. The inhibitor k rQ was cell system–independent, thereby allowing calculation of a system-independent K i. The variability in efflux-active P-gp concentrations and basolateral uptake clearances in the five laboratories was about an order of magnitude. These laboratory-to-laboratory variabilities can explain more than 60% of the IC 50 variability found in the principal component analysis plot in a previous study, supporting the hypothesis that the observed IC 50 variability is primarily due to differences in expression levels of efflux-active P-gp and the basolateral digoxin uptake transporter. HPTCs had 10- to 100-fold lower efflux-active P-gp concentrations than the overexpressing cell lines, whereas their digoxin basolateral uptake clearances were similar. HPTC basolateral uptake of digoxin was inhibited 50% by 10 μ M ouabain, suggesting involvement of OATP4C1.

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