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Running head: GRAPEFRUIT JUICE

The Grapefruit Juice Effect: Psychopharmaceutical Drugs

Elif Okan
Istanbul Bilgi University
2009
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The Grapefruit Juice Effect: Psychopharmaceutical Drugs

What is now a vast literature on the interaction effects of grapefruit juice with various
drugs can be traced back to 1989 when a team of researchers investigating the interaction of
ethanol and folodipine accidentally discovered that grapefruit juice, used with the intention of
masking the taste of ethanol, increased the blood levels of felodipine (Bailey, Spence, Edgar,
Bayliff & Arnold, 1989). This discovery drew the attention of the drug metabolism
researchers; and further studies focusing on the interaction of grapefruit and its juice with
various drugs were conducted. As a result of these studies, it is now known that something in
grapefruit inhibits an enzyme in the wall of the intestine that is responsible for the breakdown
of a number of medicines (The People’s Pharmacy, 2002). This review aims to elaborate on
the mechanisms underlying this interaction while focusing especially on the effects on
psychopharmaceutical drugs.
Studies, so far, have reported that grapefruit juice increases oral bioavailability of
many drugs including cyclosporine, terfenadine, felodipine, simvastatin and nifedipine. (e.g.
Mehrsai, Pourmand, Mansour, Zand & Rezaali, 2003; Clifford et.al., 1996; Lown et al., 1997;
Lilja, Neuvonen & Neuvonen, 2003; Adigun & Mudasiru, 2002). A common point of all these
drugs is that they are primarily metabolized by Cychtrome P450 3A4 (CYP3A4).
Consequently, most of the research on the grapefruit juice effect focuses on the modulation of
this cytochrome as it relates to elevated blood levels of various drugs. Cycthrome P450 (CYP)
enzymes system refers to a group of enzymes that are involved in drug activation and
metabolism (Engin et.al., 2009). CYP3A4, a member of the superfamily of cytochrome P450
enzymes, is responsible for the oxidation of many xenobiotics. Abundant in especially the
liver and the intestine, CYP3A4 is also reportedly the substrate of almost half of the marketed
drugs (Su, Ueng, Dung, Reddy & Wu, 2007).
The main theory on how the grapefruit juice effect occurs is based on the research
implications which indicate that a substance yet to be identified in the grapefruit directly
inhibits the activities of the cychtochrome P4503A4. This, in turn, results in an obstruction in
the breakdown process, impairs first pass metabolism, and eventually leads to higher blood
levels of the administered substance (Maskalyk, 2002). Thus, two conditions should be met
for a drug to interact with grapefruit juice: (1) the drug substrate must be predominantly
metabolized by CYP3A4; and (2) it must undergo first pass metabolism (Shimomura,
Wanwimolruk & Chen, 2003). In addition, this interaction effect is reported to be partially
irreversible. That is, because the effect of a single 8-oz glass of grapefruit juice can last for 24
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to 48 hours, taking the drug at a separate time from drinking the juice may still result in the
interaction effect (Wilkinson, 2005).
The level and/or manifestations of this effect, on the other hand, are shown to be
dependent on a number of factors including the grapefruit juice consumption patterns,
characteristics of the drug and form of drug administration. McCloskey, Zaiken and Courls
(2008) argue that repeated consumption of grapefruit juice increases the inhibitory effect, and
results in enhancement of the extent of interaction. The level of interaction can also vary
depending on some characteristics of the drugs. For example, it has been reported that even
though both nisoldipine and amlodipine are dihydropyridines; the former is more susceptible
to the grapefruit effect because it has a very low innate bioavalibility (Bailey, Malcolm,
Arnold & Spence, 1998). In addition, comparative studies have demonstrated that grapefruit
juice is only effective in orally administered drugs as compared to intravenous forms of
administration (e.g. Kupferschmidt, Fattinger, Ha, Follath & Krähenbühl, 1998). Similarly,
Bailey (2002) reports that no interactions would be expected from simultaneous intake of
grapefruit juice with parenterally or transdermally administered drugs. This, as a side note, is
mainly based on (and the basis of) the research indicating that active ingredient of the
grapefruit juice primarily functions on the intestinal, rather than hepatic, activities of CYP3A4
(Chan, Nguyen, Miller & Harris, 1998).
Elbe (n.d.) lists several medications that should be avoided or to be used with caution
with grapefruit juice. A number of these medications are widely used psychopharmaceutical
drugs; buspirone (BuSpar), bupropion (Zyban), carbamazepine (Tegretol), clomipramine
(Anafranil), diazepam (Valium), quetiapine fumarate (Seroquel), midazolam (Versed),
sertraline (Zoloft), trazodone (Desyrel), and triazolam (Halcion). The listed drugs can be
grouped under the main categories of antidepressants, anxiolytics, mood stabilizers, and
antipsychotics. These drug types are among the most frequently prescribed pharmaceuticals.
For example, one study reports that of the 2.4 billion drugs prescribed in the United States,
1.8 million were antidepressants (Cohen, 2005). Similarly, it has also been reported that about
12.5% of the United States population uses prescribed anxiolytics (Suzuki, Sola & Akinsoto,
2006). Consequently, considering the wide prescription rates, it becomes clinically vital to
further elaborate on what effects may surface when these drugs taken with grapefruit juice.
When grapefruit juice is taken with antidepressants such as amitripytline, sertraline,
trazodone, nefazodone, and clomipramine; it has been shown to increase plasma
concentrations of these drugs. Lee and colleagues (1999) conducted an in-vivo and in-vitro
study on grapefruit-juice setraline interaction, and reported that grapefruit juice causes a 50%
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bioavailability increase in sertraline. However, as Kane (2004) notes, clinical implications of

these finding are still unclear. Another study reported that co-administration of grapefruit
juice and clomipramine (a tricyclic antidepressant) results in a 4.5% increase in plasma levels
(Vandel et.al., 1999). Furthermore, the results reported by Oesterheld and Kallepalli (1997) on
clomipramine were found particularly interesting by many authors. These results indicated
that the increase in clomipramine levels caused by grapefruit juice had therapeutic effects on
two children with obsessive compulsive disorder. Keltner (2002) commented on this by
underlying the fact that the narrow therapeutic index of tricyclic antidepressants (TCAs)
makes such interaction effects particularly important.
Anxiolytic agents are reported to undergo interactions similar to those of
antidepressants – grapefruit juice increases the plasma concentrations of a number of
benzodiazepines and buspirone. For example, Kupferschmidt and colleagues (1995) reported
that the bioavailability of midazolam, which is a short-acting benzodiazepine derivative, is
enhanced by approximately 24% with the pre-intake of grapefruit juice. Authors concluded
that this finding may be clinically important for especially patients with other causes of
increased midazolam bioavilibility such as advanced age or cirrhosis of the liver. Similarly,
an in vivo study on the grapefruit juice – buspirone interaction reported significantly
increased buspirone concentrations and noted that consumption of at least large amounts of
grapefruit juice should be avoided when using this drug (Lilja, Kivistoe, Backman, Lamberg
& Neuvonen, 1998).
The number of drugs reported to be susceptible to grapefruit juice effect other than the
antidepressants and anxiolytic agents are relatively limited. One of such drugs is
carbamazepine (Tegretol) which is an anticonvulsant medicine that is also used as a mood
stabilizer in bipolar disorder treatment (Totic, Marinkovic & Marjanovic, 2008). A study with
epilepsy patients reported that grapefruit juice increases the bioavalibility of carbamazepine
(Garg, Kumar, Bhargava & Prabhakar, 1998). However, psychopharmacological effects of
this increase are yet to be investigated. Another drug that has been suggested to be effected by
grapefruit juice consumption is quetiapine fumarate (Seroquel) which is an antipsychotic
medicine used mainly in the treatment of Schizophrenia and bipolar disorder. The possible
resulting side effects are listed as drowsiness, headaches, dizziness, involuntary muscle
twitching and restlessness (The People’s Pharmacy, 2002).
In conclusion, even though there is still a need for further research on the grapefruit
juice effect on especially the psychopharmaceutical medication; the studies so far indicate the
presence and possible clinical significance of such an interaction. Until the exact mechanisms
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of action can be described for specific drugs, clinicians may be called to be cautious on the
enhancing effects of the grapefruit juice in the prescription process of especially the already
listed medication. Furthermore, informing the patients on this effect may be helpful in
preventing undesired consequences of elevated plasma levels.
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