Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug

Clin Pharmacol Ther. 2009 Feb;85(2):173-81. doi: 10.1038/clpt.2008.195. Epub 2008 Nov 5.


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, <or=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; IC(50)) were generated using Caco-2 cells for 19 P-gp inhibitors. Maximum steady-state inhibitor systemic concentration [I], [I]/IC(50) ratios, hypothetical gut concentration ([I(2)], dose/250 ml), and [I(2)]/IC(50) ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (C(max))(,i,ss)/C(max,ss) and area under the curve (AUC)(i)/AUC ratios from the clinical trials. [I]/IC(50) < 0.1 shows high false-negative rates (24% AUC, 41% C(max)); however, to a limited extent, [I(2)]/IC(50) < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC(50) > 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Amiodarone / metabolism
  • Amiodarone / pharmacology
  • Caco-2 Cells
  • Digoxin / metabolism*
  • Digoxin / pharmacology
  • Drug Interactions
  • Humans
  • Pharmaceutical Preparations / metabolism
  • Retrospective Studies


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Pharmaceutical Preparations
  • Digoxin
  • Amiodarone