Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice

Eur J Clin Pharmacol. 2008 Mar;64(3):293-301. doi: 10.1007/s00228-007-0417-y. Epub 2008 Jan 3.


Objective: To explore whether sex-related differences in intestinal itraconazole metabolism exist in healthy adults using grapefruit juice (GFJ) as a selective enteric cytochrome P450 3A4 (CYP3A4) inhibitor.

Methods: Twenty (ten female) subjects received 240 mL bottled water or single-strength GFJ from a frozen concentrate three times daily for 2 days. On day 3, the subjects received an itraconazole oral solution 200 mg with 240 mL of beverage followed 2 h later by 240 mL of the same beverage. Serial blood sampling for itraconazole and hydroxyitraconazole serum concentrations was performed over a 72-h period. After a 20-day washout, the subjects crossed over and repeated the study.

Results: Among the female subjects, GFJ reduced itraconazole weight-adjusted apparent oral clearance (Cl/F) (19%, p = 0.006) and increased AUC(0-infinity) (30%, p = 0.01), but produced no significant change in hydroxyitraconazole pharmacokinetics. In males, GFJ produced no significant change in either itraconazole, or hydroxyitraconazole pharmacokinetics. Grapefruit juice also significantly reduced the metabolite:parent AUC(0-infinity) ratio (12%, p = 0.047), in females, but not males. Itraconazole weight-adjusted oral Cl/F was significantly higher in females than males when itraconazole was administered with water (56%, p = 0.009), and although the extent to which GFJ altered itraconazole weight-adjusted oral CL/F was greater in females, it did not differ significantly between the sexes (p = 0.085).

Results: The influence of GFJ on the presystemic metabolism of itraconazole was greater in females than males. Repeated ingestion of GFJ significantly reduced itraconazole weight-adjusted oral CL/F and significantly increased exposure in females, but it produced no significant change among males. Although itraconazole weight-adjusted oral Cl/F was much higher in females than in males, the extent to which GFJ altered itraconazole weight-adjusted oral CL/F did not differ significantly between the sexes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antifungal Agents / pharmacokinetics*
  • Area Under Curve
  • Beverages
  • Citrus paradisi / chemistry*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Female
  • Food-Drug Interactions*
  • Humans
  • Itraconazole / analogs & derivatives
  • Itraconazole / blood
  • Itraconazole / pharmacokinetics*
  • Male
  • Pharmaceutical Solutions
  • Sex Factors


  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Pharmaceutical Solutions
  • hydroxyitraconazole
  • Itraconazole
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human