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

Paul O. Gubbins, Bill J. Gurley, David K. Williams, Scott R. Penzak, Scott A. McConnell, Amy M. Franks, Michael Saccente

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 AUC0-∞ (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 AUC0-∞ 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.

Original languageEnglish
Pages (from-to)293-301
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume64
Issue number3
DOIs
StatePublished - 1 Mar 2008

Keywords

  • Drug metabolism
  • Grapefruit juice
  • Itraconazole
  • Pharmacokinetics
  • Sex-related differences

Fingerprint Dive into the research topics of 'Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice'. Together they form a unique fingerprint.

  • Cite this

    Gubbins, P. O., Gurley, B. J., Williams, D. K., Penzak, S. R., McConnell, S. A., Franks, A. M., & Saccente, M. (2008). Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice. European Journal of Clinical Pharmacology, 64(3), 293-301. https://doi.org/10.1007/s00228-007-0417-y