TY - JOUR
T1 - Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice
AU - Gubbins, Paul O.
AU - Gurley, Bill J.
AU - Williams, David K.
AU - Penzak, Scott R.
AU - McConnell, Scott A.
AU - Franks, Amy M.
AU - Saccente, Michael
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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.
AB - 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.
KW - Drug metabolism
KW - Grapefruit juice
KW - Itraconazole
KW - Pharmacokinetics
KW - Sex-related differences
UR - http://www.scopus.com/inward/record.url?scp=43049165334&partnerID=8YFLogxK
U2 - 10.1007/s00228-007-0417-y
DO - 10.1007/s00228-007-0417-y
M3 - Article
C2 - 18172627
AN - SCOPUS:43049165334
SN - 0031-6970
VL - 64
SP - 293
EP - 301
JO - European Journal of Clinical Pharmacology
JF - European Journal of Clinical Pharmacology
IS - 3
ER -