Drug-Drug Interactions Mediated Through P-Glycoprotein: Clinical Relevance and In Vitro-In Vivo Correlation Using Digoxin as a Probe Drug

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the p-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, <= 100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P-gp, because of the absence of metabolic clearance. In vitro inhibitory potency data (concentration of inhibitor to inhibit 50% P-gp activity; IC50) were generated using Caco-2 cells for 19 P-gp inhibitors. maximum steady-state inhibitor systemic concentration [I], [I]/IC50 ratios, hypothetical gut concentration ([I-2], dose/250 ml), and [I-2]/IC50 ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (C-max),(i,ss)/C-max,C-ss and area under the curve (AUC)(i)/AUC ratios from the clinical trials. [I]/IC50 < 0.1 shows high false-negative rates (24% AUC, 41% C-max); however, to a limited extent, [I-2]/IC50 < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC50 > 0.1 is predictive of clinical digoxin interactions (AUC and C-max).