Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers.
OBJECTIVE
To evaluate the effect of repeated ingestion of grapefruit juice on the systemic availability of itraconazole (ITZ) and hydroxyitraconazole (OHITZ) serum concentrations in subjects administered hydroxypropyl-beta-cyclodextrin-ITZ (HP-beta-CD ITZ) oral solution.


METHODS
Randomized, two-period, crossover study.


METHODS
College of pharmacy research unit.


METHODS
Twenty healthy, adult volunteers (10 men, 10 women).


METHODS
Subjects received 240 ml of regular-strength grapefruit juice from frozen concentrate or bottled purified water 3 times/day for 2 days. On the third day they received a single dose of HP-beta-CD ITZ oral solution 200 mg (20 ml) with 240 ml of the beverage. Two hours after dosing they received another 240 ml of the beverage.


RESULTS
Repeated blood samples were drawn for 72 hours after dosing. After a 14-day washout period, subjects were crossed over to the beverage they had not received previously and the above procedure was repeated. There was no difference in peak ITZ concentration (Cmax) or time to Cmax (Tmax). Coadministration of grapefruit juice reduced OHITZ Cmax nearly 10%, but this difference was not statistically significant. It produced a statistically significant increase in ITZ area under the concentration-time curves from 0-48 hours (AUC(0-48)) (17%) and from time zero extrapolated to infinity (AUC(0-infinity)) (19.5%). Apparent oral clearance of ITZ was significantly reduced (14%). Significant changes in OHITZ exposure were not observed; however, grapefruit juice coadministration produced statistically significant decreased mean OHITZ:ITZ AUC(0-48) and AUC(0-infinity) ratios. Grapefruit juice also decreased the mean OHITZ:ITZ Cmax ratio, but the difference was not statistically significant.


CONCLUSIONS
Repeated grapefruit juice consumption moderately affects ITZ systemic availability in subjects administered HP-beta-CD ITZ oral solution. Unlike previous findings with ITZ capsules, changes in the disposition of ITZ and OHITZ after repeated grapefruit juice consumption are consistent with grapefruit juice inhibition of intestinal cytochrome P450 3A4.
Gubbins
Paul O
PO
Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock 72205-7122, USA. Gubbinspaulo@uams.edu
McConnell
Scott A
SA
Gurley
Bill J
BJ
Fincher
Timothy K
TK
Franks
Amy M
AM
Williams
David K
DK
Penzak
Scott R
SR
Saccente
Michael
M
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001628:Beverages; D001682:Biological Availability; D032083:Citrus paradisi; D018592:Cross-Over Studies; D003505:Cyclodextrins; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D019999:Pharmaceutical Solutions; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D003505:Cyclodextrins; D019999:Pharmaceutical Solutions; D047392:beta-Cyclodextrins; C084794:hydroxyitraconazole; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole