HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by Veronese, M. L. Articles by Greenberg, H. E. Search for Related Content PubMed PubMed Citation Articles by Veronese, M. L. Articles by Greenberg, H. E. Social Bookmarking                         What's this?

Exposure-Dependent Inhibition of Intestinal and Hepatic CYP3A4 In Vivo by Grapefruit Juice

From the Division of Clinical Pharmacology, Departments of Medicine and Biochemistry (Dr. Veronese, Ms. Gillen, Ms. Burke, Ms. Dorval, Dr. Hauck, Mr. Pequignot, Dr. Greenberg) and Molecular Pharmacology (Dr. Waldman), Thomas Jefferson University, Philadelphia, Pennsylvania.

Consumption of typical quantities of grapefruit juice (GFJ) increases the oral bioavailability of several CYP3A4 substrates without affecting their elimination, consistent with selective inhibition of intestinal but not hepatic CYP3A4. However, increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4. The current study compared the effects of consuming large quantities and more typical amounts of GFJ on the activity of hepatic and intestinal cytochrome P450 3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-phase, randomized, placebo-controlled crossover study, with each phase conducted with a separate panel of subjects. In Phase I, 8 male volunteers were randomized to the order of receiving one glass (240 mL) of water (placebo) or double-strength (DS) GFJ tid for 2 days and then 90, 60, and 30 minutes prior to administration of probe drugs on the 3rd day. In Phase II, 16 male volunteers were randomized to the order of receiving one glass of (1) single-strength (SS) GFJ, (2) DS GFJ, and (3) water (placebo). All treatments were administered in a fasted state. There was at least a 7-day washout period between treatments. Probe drugs, administered 30 minutes or 1 hour following each treatment in Phase I or II, respectively, consisted of oral midazolam (2 mg) coadministered with IV [¹⁴C N-methyl] erythromycin (0.03 mg). The EBT was performed 20 minutes following erythromycin administration. Blood was collected during the 24 hours following probe drug administration for the analysis of midazolam pharmacokinetics. In Phase I, consumption of one glass of DS GFJ tid for 3 days increased the C_max of midazolam 3-fold, the AUC 6-fold, and the t_1/2 2-fold and decreased the amount of exhaled ¹⁴CO₂ in all 8 subjects, with a mean decrease in EBT of 18%. In Phase II, consumption of one glass of DS GFJ significantly increased the AUC and C_max of midazolam 2-fold without a significant effect on the t_1/2 of midazolam or the EBT. The effects of consuming one glass of SS GFJ on midazolam pharmacokinetics and the EBT were not significantly different from those of one glass of DS GFJ. It was concluded that consumption of one glass of DS GFJ tid for 3 days significantly increased the AUC, C_max, and t_1/2 of midazolam and reduced EBT values, reflecting inhibition of both hepatic and intestinal CYP3A4. In contrast, consumption of one glass of SS or DS GFJ increased midazolam AUC and C_max, with little effect on the midazolam t_1/2 and EBT values, reflecting preferential inhibition of intestinal CYP3A4. Alterations of midazolam AUC and C_max induced by nine glasses of DS GFJ were significantly greater than those produced by one glass of SS or DS GFJ. These data suggest that GFJ inhibits intestinal and hepatic CYP3A4 in an exposure-dependent fashion and that patients taking medications that are CYP3A4 substrates are at risk for developing drug-related adverse events if they consume large amounts of grapefruit juice.

Key Words: Intestinal and hepatic CYP3A4 • grapefruit juice • drug metabolism • bioavailability • inhibitors of CYP3A4

Address for reprints: Howard E. Greenberg, MD, MS, FCP, Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College, 132 South 10th Street, 1170 Main, Philadelphia, PA 19107.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				X.-H. Zhu, J.-J. Jiao, C.-L. Zhang, J.-S. Lou, and C.-X. Liu Limited sampling strategy in rats to predict the inhibited activities of hepatic CYP3A Lab Anim, July 1, 2009; 43(3): 284 - 290. [Abstract] [Full Text] [PDF]

				K. M. Koch, A. P. Beelen, P. T.C. Ho, and D. F. Roychowdhury The Value of Label Recommendations: How to Dose Lapatinib J. Clin. Oncol., November 20, 2007; 25(33): 5331 - 5332. [Full Text] [PDF]

				D. Farkas, L. E. Oleson, Y. Zhao, J. S. Harmatz, M. A. Zinny, M. H. Court, and D. J. Greenblatt Pomegranate Juice Does Not Impair Clearance of Oral or Intravenous Midazolam, a Probe for Cytochrome P450-3A Activity: Comparison With Grapefruit Juice J. Clin. Pharmacol., March 1, 2007; 47(3): 286 - 294. [Abstract] [Full Text] [PDF]

				J. W. Erdman Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. Hollman, C. L. Keen, G. Mazza, et al. Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC J. Nutr., March 1, 2007; 137(3): 718S - 737S. [Abstract] [Full Text] [PDF]

				S. U. Mertens-Talcott, I. Zadezensky, W. V. De Castro, H. Derendorf, and V. Butterweck Grapefruit-drug interactions: can interactions with drugs be avoided? J. Clin. Pharmacol., December 1, 2006; 46(12): 1390 - 1416. [Abstract] [Full Text] [PDF]

				S. Uchida, H. Yamada, X. D. Li, S. Maruyama, Y. Ohmori, T. Oki, H. Watanabe, K. Umegaki, K. Ohashi, and S. Yamada Effects of ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J. Clin. Pharmacol., November 1, 2006; 46(11): 1290 - 1298. [Abstract] [Full Text] [PDF]

				E. L. Kaplan, A. P. Winston, J. C. Schoenholtz, J.-D. Harris, O. A. de Leon-Casasola, J. K. Amory, D. W. Amory Sr., W. A. Ray, K. T. Murray, C. M. Stein, et al. Oral erythromycin and the risk of sudden death. N. Engl. J. Med., January 20, 2005; 352(3): 301 - 304. [Full Text] [PDF]

				L. I Mennen, R. Walker, C. Bennetau-Pelissero, and A. Scalbert Risks and safety of polyphenol consumption Am. J. Clinical Nutrition, January 1, 2005; 81(1): 326S - 329S. [Abstract] [Full Text] [PDF]