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

Paul O. Gubbins, Pharm.D.; Scott A. McConnell, Pharm.D.; Bill J. Gurley, Ph.D.; Timothy K. Fincher, Ph.D.; Amy M. Franks, Pharm.D.; David K. Williams, Ph.D.; Scott R. Penzak, Pharm.D.; Michael Saccente, M.D.


Pharmacotherapy. 2004;24(4) 

In This Article

Abstract and Introduction

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 (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 (AUC0-48) (17%) and from time zero extrapolated to infinity (AUC0- ) (19.5%). Apparent oral clearance of ITZ was significantly reduced (14%). Significant changes in OHITZ exposure were not observed; however, grapefruit juice coadmin-istration produced statistically significant decreased mean OHITZ:ITZ AUC0-48 and AUC0- ratios. Grapefruit juice also decreased the mean OHITZ:ITZ Cmax 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.

Oral drug absorption is a complex process involving drug delivery to the intestine, absorption from the intestinal lumen, intestinal metabolism, and active extrusion.[1] Intestinal epithelium is a barrier that orally administered compounds must traverse before reaching the systemic circulation. Apical tight junctions restrict paracellular transport of large molecules (> 350 daltons) across this barrier, thus drug absorption occurs primarily by transcellular transport.[2] With a few exceptions, most orally administered drugs are absorbed by passive transcellular diffusion.[2] Thus, factors involved in delivery of oral drugs to intestinal epithelium (gastric emptying, gastric pH), or absorption from the lumen (surface area, dissolution rate, lipophilicity, particle size) have long been considered primary determinants of absorption. Intestinal phase I metabolism (cytochrome P450 [CYP] isoform 3A4) and uptake or active extrusion by transport proteins such as human organic anion transport protein (OATP) and P-glyco-protein (P-gp), respectively, are recognized as major determinants of oral drug bioavailability.[3,4]

Ingestion of grapefruit juice alters the oral availability of many agents. This interaction primarily occurs by inhibition of intestinal CYP3A4-mediated presystemic metabolism and perhaps by inhibition of active extrusion by P-gp. In addition, grapefruit juice-mediated intestinal inhibition of the uptake transporter human OATP reduces drug absorption.[5] Components in grapefruit cause rapid degradation of intestinal CYP3A4 and competitively inhibit P-gp and OATP in vitro.[4,6,7] The effects of this inhibition on orally administered CYP3A4 substrates are highly variable and difficult to predict within and between drug classes and individuals.[8] Consequently, the clinical significance of the interaction also varies and depends on the specific agent, patient, and availability of a noninteracting therapeutic alternative.[9] The clinical significance of drug interactions with grapefruit juice may be debated; nonetheless, the interactions have greatly improved the understanding of processes involved in oral drug absorption, specifically, presystemic intestinal metabolism.

Itraconazole (ITZ) is a synthetic triazole antifungal agent administered to treat superficial and systemic fungal infections caused by dermatophytes, yeasts, and certain molds. It is available as a capsule and as an oral and intravenous solution formulated in hydroxypropyl-β-cyclodextrin (HP-β-CD).[10] The drug is a highly lipophilic weak base and is practically insoluble in water. Therefore the capsule requires complete dissolution in the gastric contents for optimal absorption into systemic circulation.[11] The presence of food facilitates intestinal absorption of ITZ from the capsule. Even under fed conditions, however, ITZ is erratically absorbed from the capsule, and its pharmacokinetics show marked interindividual variations with this dosage form.[12] Hydroxypropyl-b-CD significantly enhances the solubility of ITZ. The oral solution is absorbed rapidly because it requires no dissolution in the stomach. As a result, high ITZ concentrations are delivered to intestinal epithelium, which may cause transient saturation of intestinal CYP3A4.[13,14] Under fasting conditions, absorption of ITZ from the oral solution is more rapid than in the presence of food. Consequently, peak plasma concentrations of both ITZ and its primary metabolite, hydroxyitraconazole (OHITZ), are higher and are achieved earlier compared with nonfasting conditions.[13,14] In the absence of food ITZ is absorbed more rapidly and completely from the oral solution than from the capsule under fed conditions, which results in a pharmacokinetic profile with less interpatient and intrapatient variability.[15]

Findings from a crossover study suggested that absorption of ITZ from the capsule dosage form is decreased and delayed with coadministration of double-strength grapefruit juice (concentrated juice reconstituted with half the recommended amount of water).[16] In the current study we hypothesized that the systemic availability of ITZ oral solution may be less affected by grapefruit juice because of its enhanced absorption and possible saturation of intestinal CYP3A4.


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