Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice.
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.
Gubbins
Paul O
PO
College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7122, USA. gubbinspaulo@uams.edu
Gurley
Bill J
BJ
Williams
David K
DK
Penzak
Scott R
SR
McConnell
Scott A
SA
Franks
Amy M
AM
Saccente
Michael
M
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001628:Beverages; D032083:Citrus paradisi / Q000737:chemistry*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D019999:Pharmaceutical Solutions; D012737:Sex Factors
D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D019999:Pharmaceutical Solutions; C084794:hydroxyitraconazole; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human