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

Abstract

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 ([I2], dose/250 ml), and [I2]/IC50 ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (Cmax),i,ss/Cmax, 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% Cmax); however, to a limited extent, [I2]/IC50 < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC50 > 0.1 is predictive of clinical digoxin interactions (AUC and Cmax). Clinical Pharmacology & Therapeutics (2009); 85, 2, 173–181 doi:10.1038/clpt.2008.195