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DRUG METABOLISM |
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
Cmax of midazolam 3-fold, the AUC 6-fold, and the t1/2
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 Cmax of
midazolam 
2-fold without a significant effect on the t1/2 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, Cmax, and
t1/2 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 Cmax, with little effect
on the midazolam t1/2 and EBT values, reflecting preferential
inhibition of intestinal CYP3A4. Alterations of midazolam AUC and
Cmax 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.
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