Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein

Br J Clin Pharmacol. 2006 May;61(5):538-44. doi: 10.1111/j.1365-2125.2006.02613.x.


Aims: Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers.

Methods: In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing.

Results: Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine.

Conclusions: Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Adult
  • Analysis of Variance
  • Cross-Over Studies
  • Diltiazem / pharmacology*
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacokinetics*
  • Histamine H1 Antagonists / urine
  • Humans
  • Itraconazole / pharmacology*
  • Male
  • Terfenadine / analogs & derivatives*
  • Terfenadine / blood
  • Terfenadine / pharmacokinetics
  • Terfenadine / urine
  • Time Factors


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Histamine H1 Antagonists
  • Itraconazole
  • Terfenadine
  • fexofenadine
  • Diltiazem