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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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 \({\text{AUC}}_{0 - \infty } \) (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 \({\text{AUC}}_{{\text{0 - }}\infty } \) 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.

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Acknowledgments

The authors wish to acknowledge Kathleen McConnell for assistance in indwelling vascular catheter placement. This work was made possible by a Grant from Glaxo-Wellcome in conjunction with The American College of Clinical Pharmacy (ACCP) Research Institute, Pharmacotherapy 1998 Research Award Program.

Conflict of interest statement

There are no actual or potential conflicts of interest on the part of any author or their respective institution in terms of financial or personal relationships that could influence or could be perceived to influence the work.

Author information

Authors and Affiliations

  1. College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205-7122, USA

    Paul O. Gubbins, Bill J. Gurley & Amy M. Franks

  2. College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    David K. Williams

  3. College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    David K. Williams & Michael Saccente

  4. Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W. Markham #522, Little Rock, AR, 72205-7122, USA

    Paul O. Gubbins & Amy M. Franks

  5. Department of Pharmaceutical Sciences, Little Rock, AR, USA

    Bill J. Gurley

  6. Division of Biometry, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    David K. Williams

  7. Division of Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Michael Saccente

  8. Cubist Pharmaceuticals, Omaha, NE, USA

    Scott A. McConnell

  9. Department of Pharmacy Practice, College of Pharmacy, Creighton University, Omaha, NE, USA

    Scott A. McConnell

  10. Clinical Pharmacokinetics Lab, Department of Pharmacy, NIH Clinical Center, Bethesda, MD, USA

    Scott R. Penzak

Authors
  1. Paul O. Gubbins
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  2. Bill J. Gurley
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  3. David K. Williams
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  4. Scott R. Penzak
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  5. Scott A. McConnell
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  6. Amy M. Franks
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  7. Michael Saccente
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Corresponding author

Correspondence to Paul O. Gubbins.

Additional information

This work was presented in part at the American College of Clinical Pharmacy Annual Meeting, October 25, 1999, Kansas City, Missouri and at the 40th Interscience Conference of Antimicrobial Agents and Chemotherapy, September 18, 2000, Toronto Canada.

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Gubbins, P.O., Gurley, B.J., Williams, D.K. et al. Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice. Eur J Clin Pharmacol 64, 293–301 (2008). https://doi.org/10.1007/s00228-007-0417-y

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  • DOI: https://doi.org/10.1007/s00228-007-0417-y

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