Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics

Clin Pharmacol Ther. 2005 Jan;77(1):17-23. doi: 10.1016/j.clpt.2004.08.026.


Objective: Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics.

Methods: Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing.

Results: Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment.

Conclusion: This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Area Under Curve
  • Biological Availability
  • Calcium Channel Blockers / pharmacology*
  • Cimetidine / pharmacology*
  • Drug Interactions
  • Half-Life
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacokinetics*
  • Histamine H1 Antagonists / urine
  • Histamine H2 Antagonists / pharmacology*
  • Humans
  • Male
  • Probenecid / pharmacology*
  • Terfenadine / analogs & derivatives*
  • Terfenadine / blood
  • Terfenadine / pharmacokinetics*
  • Terfenadine / urine
  • Uricosuric Agents / pharmacology*
  • Verapamil / pharmacology*


  • Calcium Channel Blockers
  • Histamine H1 Antagonists
  • Histamine H2 Antagonists
  • Uricosuric Agents
  • Terfenadine
  • Cimetidine
  • Verapamil
  • fexofenadine
  • Probenecid