The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique

Br J Clin Pharmacol. 2003 Feb;55(2):182-90. doi: 10.1046/j.1365-2125.2003.01722.x.


Aims: To investigate whether the drug-drug interaction between fexofenadine and ketoconazole is localized to efflux transport proteins of the small intestine, and to determine and classify the effective jejunal permeability (Peff) of fexofenadine according to the Biopharmaceutics Classification System (BCS).

Methods: Two separate jejunal perfusion experiments were performed using the Loc-I-Gut technique in eight healthy volunteers. During treatment 1 (T1), we investigated the acute effect of ketoconazole on the Peff and plasma pharmacokinetics of fexofenadine. In treatment 2 (T2) we examined the effect of oral pretreatment with ketoconazole (200 mg daily for 5 days) on the same absorption parameters. Each experiment was divided into two periods of 100 min and the jejunal segment was perfused with 93 micro m fexofenadine during both periods. In period 2 of each treatment, fexofenadine was coadministered with 94 micro m ketoconazole. The concentrations of fexofenadine in intestinal perfusate and plasma were measured by liquid chromatography with mass detection.

Results: During T1, the mean (+/- s.d.) Peff of fexofenadine was low according to the BCS (0.11 +/- 0.11 and 0.04 +/- 0.13 x 10(-4) cm s(-1) in periods 1 and 2, respectively), and the coadministration of ketoconazole in period 2 had no significant acute effect on Peff (95% confidence interval (CI) on the difference -0.37, 0.51). After pretreatment with ketoconazole (T2), the jejunal Peff of fexofenadine increased to 0.29 +/- 0.47 and 0.22 +/- 0.31 x 10-4 cm s(-1) in both periods 1 and 2, respectively, but the change was not statistically significant when compared with T1 (95% CI on the difference -0.62, 0.27 for T1 0-100 min vs T2 0-100 min; -0.54, 0.34 for T1 0-100 min vs T2 100-200 min). Fexofenadine plasma AUC from 0-100 mg showed no significant difference after pretreatment with ketoconazole (55 +/- 101 and 51 +/- 33 micro g ml(-1) min(-1) respectively; 95% CI on the difference -108, 115). Total plasma AUC (0-720 min) was 318 +/- 426 and 426 +/- 232 ng ml(-1) min in T1 and T2, respectively (95% CI on the difference -622, 405).

Conclusions: No significant effect of acute coadministration or pretreatment with ketoconazole on the in vivo intestinal absorption of fexofenadine was detected in this study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antifungal Agents / pharmacology*
  • Biological Availability
  • Chromatography, High Pressure Liquid
  • Cross-Over Studies
  • Drug Interactions
  • Female
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Intestinal Absorption
  • Jejunum / physiology
  • Ketoconazole / pharmacology*
  • Male
  • Permeability
  • Terfenadine / analogs & derivatives*
  • Terfenadine / pharmacokinetics*


  • Antifungal Agents
  • Histamine H1 Antagonists
  • Terfenadine
  • fexofenadine
  • Ketoconazole