Influence of Grapefruit Juice on the Systemic Availability of Itraconazole Oral Solution in Healthy Adult Volunteers

Study 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-β-cyclodextrin-ITZ (HP-β-CD ITZ) oral solution. Design. Randomized, two-period, crossover study. Setting. College of pharmacy research unit. Subjects. Twenty healthy, adult volunteers (10 men, 10 women). Intervention. 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-β-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. Measurements and Main 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 (C_max) or time to C_max (T_max). Coadministration of grapefruit juice reduced OHITZ C_max 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-∞) (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-∞ ratios. Grapefruit juice also decreased the mean OHITZ:ITZ C_max ratio, but the difference was not statistically significant. Conclusion. Repeated grapefruit juice consumption moderately affects ITZ systemic availability in subjects administered HP-β-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.