P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil

Pharmacol Res. 1999 Oct;40(4):301-6. doi: 10.1006/phrs.1999.0535.


Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with verapamil. Verapamil can increase the plasma concentration of digoxin up to 60-90%. So far the precise mechanism of this pharmacokinetic drug-drug interaction is not known. Many studies suggest that verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin-verapamil interaction. Current knowledge suggest that the non-competitive digoxin-verapamil interaction is due to inhibition of P-glycoprotein activity by verapamil resulting in a decreased renal tubular elimination of digoxin.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Anti-Arrhythmia Agents / pharmacokinetics*
  • Anti-Arrhythmia Agents / therapeutic use
  • Cardiotonic Agents / pharmacokinetics*
  • Cardiotonic Agents / therapeutic use
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Digoxin / therapeutic use
  • Drug Interactions / physiology
  • Drug Resistance, Multiple / physiology
  • Heart Failure / drug therapy
  • Humans
  • Verapamil / pharmacokinetics*
  • Verapamil / therapeutic use


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Arrhythmia Agents
  • Cardiotonic Agents
  • Digoxin
  • Verapamil