Br J Clin Pharmacol 1998; 46: 101–110

Grapefruit juice–drug interactions

David G. Bailey, J. Malcolm, O. Arnold & J. David Spence
Departments of Medicine, London Health Sciences Centre and Pharmacology and Toxicology, University of Western Ontario, London, Ontario

The novel finding that grapefruit juice can markedly augment oral drug bioavailability
was based on an unexpected observation from an interaction study between the
dihydropyridine calcium channel antagonist, felodipine, and ethanol in which
grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations
showed that grapefruit juice acted by reducing presystemic felodipine metabolism
through selective post-translational down regulation of cytochrome P450 3A4
(CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit
juice can last 24 h, repeated juice consumption can result in a cumulative increase
in felodipine AUC and Cmax. The high variability of the magnitude of effect among
individuals appeared dependent upon inherent differences in enteric CYP3A4
protein expression such that individuals with highest baseline CYP3A4 had the
highest proportional increase. At least 20 other drugs have been assessed for an
interaction with grapefruit juice. Medications with innately low oral bioavailability
because of substantial presystemic metabolism mediated by CYP3A4 appear affected
by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyri-
dines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and
may also occur with lovastatin, cisapride and astemizole. The importance of the
interaction appears to be influenced by individual patient susceptibility, type and
amount of grapefruit juice and administration-related factors. Although in vitro
findings support the flavonoid, naringin, or the furanocoumarin, 6∞,7∞-dihydroxyber-
gamottin, as being active ingredients, a recent investigation indicated that neither of
these substances made a major contribution to grapefruit juice-drug interactions
in humans.
Keywords: grapefruit juice, drug interaction, CYP3A4, intestinal drug metabolism,
pharmacokinetics, pharmacodynamics

was the most effective. The combination of a non-

Introduction
intoxicating dose of ethanol and felodipine resulted in lower
The opportunity for a food-drug interaction is an everyday standing blood pressure and a high frequency of orthostatic
occurrence. The interaction can be particularly important hypotension compared with felodipine alone in patients
when total drug absorption is altered. Recently, a chance with untreated borderline hypertension [2]. Although plasma
observation led to the finding that grapefruit juice can felodipine concentrations were not different between treat-
markedly increase the oral bioavailability of a number of ments, they were several-fold higher than observed in other
medications [1]. This article retraces discovery of this novel pharmacokinetic investigations with the same dose of drug.
interaction and reviews the mechanism of action, summaries A systematic examination for obvious possible causes, such
both studied and predicted medications for an interaction, as incorrect dose or drug assay problems, did not resolve
discusses possible active ingredient(s) in the juice and this discrepancy and eventually resulted in a pilot project in
considers clinical implications. a single volunteer to judge the role of the juice. Plasma
felodipine concentrations were more than five-fold greater
with grapefruit juice compared with water (Figure 1).
Discovery
Originally, a study was designed to test for an interaction
Mechanism
between ethanol and the dihydropyridine calcium channel
antagonist, felodipine [2], an analogue of nifedipine.
Felodipine disposition and metabolism
Grapefruit juice was chosen to mask the taste of the ethanol
following an assessment of every juice in a home refrigerator Felodipine has been the most extensively studied probe for
one Saturday evening. White grapefruit juice, particularly grapefruit juice—drug interactions. Normally, felodipine is
double-strength juice (single dilution of frozen concentrate), completely absorbed from the gastrointestinal tract following
oral administration [3]. However, it undergoes high presys-
Correspondence: Dr David G. Bailey, Department of Medicine, London Health
Sciences Centre, Victoria Campus, 375 South Street, London, Ontario, Canada, temic (first-pass) metabolism resulting in low absolute
N6A 4G5. bioavailability averaging 15% [3] but ranging from 4% to

© 1998 Blackwell Science Ltd 101

D. G. Bailey et al.

36% among individuals [4]. Both the gut wall and the liver De-esterification Cl
appear responsible for presystemic felodipine elimination [5] Cl
(Figure 2). Cl Cl HOOC COOCH3
Felodipine has a single primary metabolite, dehydrofelodi-
Cl P4503A4 Cl H3C CH3
pine [6], generated by cytochrome P450 3A4 (CYP3A4; H COOCH
N
H5C2OOC H5C2OOC COOCH3 M3 metabolite
Figure 3) [7]. Dehydrofelodipine is inactive and oxidized by *
3

Aromatization
two secondary pathways. The major secondary metabolite, H3C N CH3 H3C N CH3
M3, is also produced by CYP3A4 [8]. Apical enterocytes of H Dehydrofelodipine
the small bowel and hepatocytes of the liver both contain Felodipine
Further
CYP3A4 [9, 10]. The content of CYP3A4 in both tissues inactive
Side chain metabolites
hydroxylation
100
Figure 3 Pathways of felodipine metabolism.
concentration (nmol l–1)
Plasma felodipine

ranges at least 10-fold among individuals and appears to be

regulated independently of the other [11].
10
Grapefruit juice effects
The first report of this interaction revealed that grapefruit
juice, but not orange juice, tripled mean plasma felodipine
0 area under the curve (AUC) compared to water in borderline
0 1 2 3 4 5 6 hypertensive patients [12]. Blood pressure reduction, heart
Time (h) rate increase and frequency of vasodilatation-related adverse
Figure 1 Plasma felodipine concentration-time profile from the events were also greater. Grapefruit juice markedly elevated
pilot study in which the effect of grapefruit juice was evaluated in plasma peak felodipine concentration (Cmax ) but did not
one of the authors (DGB). Felodipine 5 mg regular tablet was alter systemic felodipine elimination half-life (t1/2 ) [12].
administered with 350 ml double-strength grapefruit juice (&) or Since grapefruit juice did not change intravenous felodipine
water (%). pharmacokinetics [5], it indicates that the interaction with
grapefruit juice resulted from inhibition of presystemic drug
Felodipine metabolism.
unmetabolized dose Grapefruit juice reduced dehydrofelodipine/felodipine
B * Grapefruit juice affected AUC ratio and increased absolute dehydrofelodipine AUC
[1, 12]. The decrease in the AUC ratio was compatible
with inhibition of the primary metabolic pathway. The
absolute increase in dehydrofelodipine AUC indicated that
a subsequent metabolic pathway might also be inhibited and
this was supported by measurements showing that the M3
metabolite AUC was reduced [8]. Thus, grapefruit juice
appeared to inhibit CYP3A4, an important isozyme of
cytochrome P450 since it oxidizes a broad range of drugs
and xenobiotics [13], with predominant and perhaps
exclusive action on presystemic drug elimination.
Recently, the effect of grapefruit juice on drug metaboliz-
A ing enzymes of the small bowel and liver was reported in
an in vivo investigation in humans [14]. Grapefruit juice
consumption for 5 days caused a mean 62% reduction of
small bowel enterocyte CYP3A4 and CYP3A5 protein
content associated with a greater than 3- and 5-fold increase
in felodipine AUC and Cmax, respectively. In contrast, liver
CYP3A4 activity, as measured by the erythromycin breath
test, and colon CYP3A5 protein content were not altered.
Also, intestinal CYP2D6 and CYP1A1 protein content were
not affected. Although these changes were measured after 5
days of grapefruit juice, preliminary data also showed that
Figure 2 Sequential presystemic felodipine metabolism by
small bowel CYP3A4 can be markedly reduced 4 h after a
CYP3A4 in apical enterocytes of the small bowel (A) and the
hepatocytes of the liver (B) in the absence and presence of single glass of juice. Consequently, it was concluded that
grapefruit juice. The percent of unmetabolized felodipine is grapefruit juice acted by selectively inhibiting CYP3A
presented before and after passage through the gut wall and the isozymes of the small bowel to cause greater felodipine oral
liver. Grapefruit juice selectively inactivated CYP3A4 in apical bioavailability.
enterocytes. Decreased expression of CYP3A isoforms by grapefruit

102 © 1998 Blackwell Science Ltd Br J Clin Pharmacol, 46, 101–110

 Grapefruit juice—drug interactions

juice implied that the interaction was not simple competition grapefruit juice than with a dihydropyridine with normally
for substrate metabolism. Since small bowel CYP3A4 high oral bioavailability. Nisoldipine [19] and amlodipine
mRNA was not changed [14], grapefruit juice likely [27] are examples of dihydropyridines with very low and
decreased CYP3A4 protein content by a post-transcriptional very high innate oral bioavailability, respectively. Mean
mechanism, possibly involving accelerated CYP3A4 degra- (range) drug Cmax for nisoldipine was 406% (107%–836%)
dation through mechanism-based enzyme inhibition. Thus, [19] and for amlodipine was 115% (79%–165%) [27] with
the return of CYP3A4 activity would require de novo grapefruit juice compared with water. Thus, nisoldipine did
enzyme synthesis which could result in prolonged effect of have a much greater fold increase of plasma drug con-
grapefruit juice. centrations compared with amlodipine. Furthermore, inter-
The duration of activity of grapefruit juice has been individual variability of the interaction was larger for
studied. In one study, consumption of a single glass (200 ml) nisoldipine which highlights the unpredictability of the
of juice at various time intervals before felodipine showed interaction among individuals for dihydropyridines with
that the extent of increase in felodipine AUC and Cmax was low oral bioavailability.
maximal between simultaneous and 4 h previous juice All dihydropyridines, apart from nifedipine, have a
administration with drug [15]. Then, the magnitude of the chiral centre with activity primarily residing with a particular
interaction declined slowly with increasing time interval enantiomer [6]. The relevance of an interaction with
between grapefruit juice and felodipine administration. The grapefruit juice then depends mostly on the magnitude of
half-life of effect of grapefruit juice was estimated at 12 h. increase of the more active enantiomer. For nitrendipine,
Higher felodipine Cmax was still evident when grapefruit the S-enantiomer possesses the activity [30, 31]. Grapefruit
juice was consumed 24 h before felodipine. In another juice produced proportional enhancement of both enanti-
investigation, the effect of routine grapefruit juice consump- omers indicating that the increase in plasma total nitrendipine
tion was evaluated [14]. One glass (250 ml) of grapefruit concentration was predictive of the pharmacodynamic extent
juice augmented mean felodipine AUC and Cmax to 267% of interaction [22]. For nicardipine, the S-enantiomer has
and 345%, respectively, of that compared with water. one-third the activity of the R-enantiomer [32]. Grapefruit
Grapefruit juice three times daily with meals for 5 days juice augmented S-nicardipine AUC and Cmax by 1.5-and
further increased felodipine AUC and Cmax to 345% and 1.2-fold more than R-nicardipine demonstrating that the
538% of that compared with water showing a cumulative effect on plasma total nicardipine concentration may slightly
effect of the juice. overestimate associated clinical consequences [21]. The
The magnitude of the interaction was highly variable S-enantiomer of non-dihydropyridine calcium channel
among individuals ranging from no change to six-fold antagonist, verapamil, has at least 10 times the dromotropic
greater plasma felodipine AUC and Cmax with grapefruit activity compared with the R-enantiomer [33]. Grapefruit
juice compared with water under single dose conditions [1, juice produced less than a doubling of mean plasma total
8, 14, 16]. However, it was reproducible within individuals verapamil AUC and Cmax [34]. However, first degree heart
following repeat testing and thus, dependent on factors block (PR interval >240 ms) was observed in only subjects
inherent to the individual [16]. Grapefruit juice reduced (4 of 24) who received verapamil with grapefruit juice.
small bowel CYP3A4 content contingent upon pretreatment Although inter-subject variation of the interaction was not
levels [14]. Individuals with the highest small bowel CYP3A4 reported, grapefruit juice may preferentially augment
content before grapefruit juice had the largest reduction in S-verapamil and thus, the increase in plasma total verapamil
CYP3A4 and highest increase in felodipine Cmax with concentrations would underestimate the importance of the
grapefruit juice. Consequently, individual disparity in the interaction.
magnitude of interaction with grapefruit juice appears at The non-sedating antihistamine, terfenadine, undergoes
least partially explained by innate differences in baseline nearly complete presystemic elimination mediated by
small bowel CYP3A4 protein content. CYP3A4 [35, 36] and is often not detected in plasma. One
of the primary metabolites, terfenadine carboxylate, accounts
for the activity [36]. Terfenadine, like quinidine, is a potent
Drugs interacting with grapefruit juice
blocker of myocyte delayed rectifier potassium current
whereas terfenadine carboxylate is devoid of this effect
Summary of studied drugs
[37–39]. Plasma terfenadine concentrations can be measured
Most medications investigated for an interaction with with overdose, liver disease or inhibition of CYP3A4
grapefruit juice are substrates for CYP3A4 (Table 1). The metabolism by concomitant administration of ketoconazole,
most extensively studied are the dihydropyridine calcium erythromycin or itraconazole and are associated with
channel antagonists. In addition to felodipine [5, 8, 12, prolongation of the QTc interval and development of a
14–18], these include nisoldipine [19], nimodipine [20], serious ventricular tachyarrhythmia, torsades de pointes
nicardipine [21], nitrendipine [22, 23], nifedipine [12, [40–52]. Approximately 125 deaths linked to terfenadine
24–26], and amlodipine [27, 28], which have similar have been reported [53]. Controlled clinical investigations
pathways of metabolism [6], but vary markedly in absolute have shown that grapefruit juice augmented plasma terfenad-
oral bioavailability dependent upon extent of presystemic ine concentrations [54–57]. A small increase in the QTc
drug elimination [29]. interval was demonstrated [54, 55]. The magnitude of the
Based on the previous discussion, it would be expected interaction was similar to that produced by itraconazole or
that a dihydropyridine with low inherent oral bioavailability erythromycin [56]. A fatality has been attributed to
would have a greater magnitude of the interaction with terfenadine toxicity after consuming the drug with grapefruit

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D. G. Bailey et al.

Table 1 Innate oral drug bioavailability

Bioavailability Medication Drug AUC Drug Cmax and mean relative drug AUC and Cmax
with grapefruit juice compared with
<5% Nisoldipine [19] 198 406 control (%) among studies.
Nimodipine [20] 151 124
Terfenadine [54–57] 249 343
Saquinavir [73] 150–220 —
15–20% Felodipine [5, 8, 12, 14–18] 145–345 170–538
Nicardipine [21] 134–196 125–153
Nitrendipine [22, 23] 140–206 140–199
Propafenone [79] 133 123
17b-oestradiol [82] 116 131
30–40% Cyclosporin [65–71] 108–162 104–132
Diltiazem [80] 110 102
Ethinylestradiol [81] 128 137
Midazolam [62] 152 156
Triazolam [63] 148 130
Verapamil [34] 143 161
60% Nifedipine [12, 24–26] 134–203 104–194
70% Quinidine [75] 108 93
>80% Acenocoumarol [74] 98 —
Amlodipine [27, 28] 108–116 115
Prednisone [69] 150 139
Theophylline [76] 103 97

Statistically significant increases in drug AUC and Cmax are indicated in bold. All medications are
substrates for CYP3A4 except for prednisone and theophylline.

juice [58]. Since there appears to be little benefit from of grapefruit juice on cyclosporin pharmacokinetics varied
taking grapefruit juice with terfenadine and there is the among studies. Plasma cyclosporin AUC [68, 70, 71] and
potential for a serious adverse interaction, regardless of the trough concentration [67, 70], which is commonly used
frequency of occurrence, it seems wise to advise against during therapeutic drug monitoring, were augmented in
grapefruit juice consumption during therapy with some investigations. The largest mean interaction was a
terfenadine. cyclosporin AUC and trough concentration with grapefruit
Midazolam and triazolam are two ultra-short acting juice that were 134% and 177%, respectively, of that
benzodiazepine hypnotics with high presystemic drug compared with water [70]. There was more than a tripling
metabolism. For midazolam, a substantial portion of presys- in plasma trough cyclosporin concentration in at least one
temic metabolism appears to occur in the small bowel [59, patient which undoubtedly is clinically important [71].
60] and the major primary metabolite, 1∞-hydroxymidazolam, Because cyclosporin is very expensive, administration with
is generated by CYP3A4 [61]. Grapefruit juice increased grapefruit juice has been suggested as a technique to decrease
mean midazolam AUC and Cmax by an estimated 41% drug costs [66]. However, the magnitude of the effect is
selective decrease of prehepatic midazolam metabolism [62]. variable among patients and the constancy of the interaction
Psychometric tests showed greater patient impairment when with repeat dosing has not been documented. Thus,
oral midazolam was administered with grapefruit juice concurrent administration of grapefruit juice cannot presently
compared with water. Similarly, grapefruit juice augmented be recommended as a therapeutic strategy for such patients
triazolam AUC and Cmax to produce enhanced drowsiness [72].
[63]. The anti-AIDS drug, saquinavir, belongs to a new class
Cyclosporin is the cornerstone of immunosuppression of agents known as protease inhibitors. Its very low
therapy following transplantation. Plasma cyclosporin con- bioavailability is in part due to presystemic metabolism by
centrations must be maintained within a narrow range to CYP3A4. A glass of regular-strength grapefruit juice
achieve adequate immunosuppression without nephrotoxic- augmented saquinavir AUC to 150% of that with water in
ity. However, cyclosporin possesses low and variable oral HIV-negative volunteers [73]. Double-strength grapefruit
bioavailability. Although this has been attributed to poor juice enhanced saquinavir AUC to 220%. Since saquinavir
drug solubility and diffusion characteristics, more recent has a wide therapeutic window, concomitant administration
work has supported presystemic cyclosporin metabolism as of grapefruit juice has been suggested as a strategy to increase
a factor [64]. In two studies of healthy volunteers, grapefruit saquinavir bioavailability. Although the magnitude of the
juice produced mean oral cyclosporin AUCs which were interaction may be variable among patients, there appears to
162% and 143% of that with water [65, 66]. Orange juice be only the potential for enhanced therapeutic benefit.
did not augment cyclosporin AUC [66]. Several studies Grapefruit juice did not interact with a number of other
were conducted in medically stable renal transplant patients medications. These include prednisone [69], acenocoumarol
[67–71]. Grapefruit juice was given with the patient’s usual [74], quinidine [75] and theophylline [76]. This is not
oral dose of cyclosporin to achieve steady state. The effect unexpected since these drugs already have high or almost

104 © 1998 Blackwell Science Ltd Br J Clin Pharmacol, 46, 101–110

 Grapefruit juice—drug interactions

complete oral bioavailability. Prednisone and theophylline does not appear to be altered by grapefruit juice [14], a
are also not substrates for CYP3A4. However, grapefruit major mechanism for systemic drug inactivation is not
juice did prolong the systemic elimination half-life of jeopardized. However, the persistence of hepatic CYP3A4
caffeine, a probe for CYP1A2 activity, and theophylline is activity means that it would not likely be possible to
metabolized by CYP1A2 [77]. This discrepancy for theo- produce complete oral drug bioavailability.
phylline may be resolved by a recent report suggesting that Flavonoids can inhibit drug oxidative metabolism [96].
grapefruit juice decreased caffeine elimination by inhibition Naringin (Figure 4) is the most prevalent flavonoid in
of flavin-containing monooxygenase, a P450 independent grapefruit juice attaining relatively high concentrations
−1
system which does not appear to metabolize theophylline (1 mmol l ) and is absent from orange juice [97] which
[78]. Other medications not showing an interaction with did not produce the interaction [12, 66]. Naringin inhibited
grapefruit juice include propafenone [79], diltiazem [80], in vitro felodipine and nifedipine metabolism but was much
ethinyloestradiol [81] and 17b-oestradiol [82]. Although less potent than its aglycone, naringenin [89, 99]. Although
they undergo presystemic metabolism, it appears that a naringenin is not normally present in grapefruit juice [97],
substantial portion is by pathways not mediated by CYP3A4. oral administration of grapefruit juice resulted in renal
excretion of naringenin conjugates demonstrating in vivo
formation of this potentially active species [100]. Also,
Drugs predicted to interact with grapefruit juice
naringenin was not detected in plasma and the total amount
The HMG-CoA reductase inhibitor, lovastatin, has been recovered in urine represented only a small percentage of
reported to produce a serious adverse skeletal muscle effect, the oral naringin dose in the juice [100], suggesting that
rhabdomyolysis, when administered with drugs that inhibit naringenin has low systemic availability which is consistent
CYP3A4 including itraconazole [83], erythromycin [84] and with inhibition of drug metabolism localized to the small
cyclosporin [85]. Lovastatin is a prodrug which normally bowel. Nevertheless, commercially-available pure naringin,
undergoes extensive presystemic elimination [86]. Less than administered in the same amount as found in grapefruit
5% of lovastatin is hydrolyzed to the pharmacologically juice, produced little or no increase in the plasma concen-
active metabolite, lovastatin acid, with the majority trations of felodipine [18] or nisoldipine [19].
biotransformed by other primary routes mediated by A furanocoumarin, 6∞,7∞-dihydroxybergamottin, has been
CYP3A4 [87]. Lovastatin and active metabolite AUCs were recently proposed as an active ingredient in grapefruit juice
increased more than twenty-fold when administered with [101]. It and a related dimer caused a dose-dependent fall in
itraconazole suggesting the adverse effect has a pharmaco- CYP3A4 catalytic activity and immunoreactive CYP3A4
kinetic basis [86]. Rhabdomyolysis has also been reported protein concentration in a Caco-2 cell culture model of
with simvastatin [88, 89] and pravastatin [90, 91]. Thus, a human intestinal epithelium [102]. The concentration of
clinically important interaction may occur between grapefruit 6∞,7∞-dihydroxybergamottin in grapefruit juice exceeded the
juice and lovastatin and possibly other HMG-CoA reductase IC50 for loss of CYP3A4 activity. CYP1A1 and CYP2D6
inhibitors. protein content were not affected. 6∞,7∞-Dihydroxyberga-
Prolonged QT interval, torsade de pointes and fatal mottin acted initially by competitive inhibition followed by
arrhythmia have been reported with the gastrointestinal mechanism-based inactivation of recombinant CYP3A4
prokinetic agent, cisapride [92]. Adverse events occurred in consistent with the in vivo effects observed in humans.
conditions where plasma cisapride concentrations were Recently a study was reported that tested the hypothesis
elevated, particularly with concomitant administration of that naringin and/or 6∞,7∞-dihydroxybergamottin in grape-
medications that inhibit CYP3A4. Cisapride normally
undergoes presystemic metabolism by CYP3A4 resulting in
OH
a 40–50% absolute oral bioavailability [93]. Torsade de
pointes has also been observed with the non-sedating rhamnoglucose O
O
antihistamine, astemizole, when administered with ketocona- *
zole [94]. Astemizole has high presystemic elimination by
three major metabolic routes to produce an estimated 3%
oral bioavailability [95]. Unless medical condition warrants OH O
their use, it might be prudent to avoid the combination of
grapefruit juice with cisapride or astemizole. Naringin

Active ingredient(s) in grapefruit juice O O

O
Identification of the active ingredient(s) in grapefruit juice
would permit evaluation of this type of interaction with
CH3
other foods. The apparently non-toxic active ingredient(s)
in grapefruit juice might be also used commercially to dose O CH2CH C CH2 CH2 CH C CH3
orally drugs that are currently active only by the intravenous CH3 OH OH
route because of complete presystemic metabolism involving
CYP3A4 or to produce higher and more dependable drug 6’, 7’ – dihydroxybergamottin
bioavailability and clinical response among or within Figure 4 Chemical structure of naringin and 6∞,7∞-
individuals [1]. In addition, because hepatic CYP3A4 activity dihydroxybergamottin.

© 1998 Blackwell Science Ltd Br J Clin Pharmacol, 46, 101–110 105

D. G. Bailey et al.

fruit juice are primarily responsible for the interaction with suggestion of adverse outcome for hypertensives treated
felodipine in humans [103]. The approach was to separate with immediate release dihydropyridines would argue that
grapefruit juice by centrifugation and ultrafiltration into a rapid increase in plasma dihydropyridine concentration by
supernatant and particulate fractions. Then, the effect on grapefruit juice, even with the extended release formulation
oral felodipine pharmacokinetics of these fractions, of [5, 8, 14–16], may put these patients at risk of ischaemic
grapefruit juice containing a comparable amount of both complications [107–110]. Also, terfenadine with grapefruit
fractions and of water were compared in healthy male juice may have increased chance of producing torsades de
volunteers. Because the amounts of naringin and 6∞,7∞- pointes in individuals with pre-existing prolonged QT
dihydroxybergamottin were found to be greater in the interval.
supernatant fraction (148 mg and 1.85 mg, respectively) than Grapefruit juice type and amount are also important
the particulate fraction (7 mg and 0.60 mg, respectively), it considerations. Commercial white grapefruit juice from
was postulated that the activity of the supernatant fraction frozen concentrate [5, 12, 14, 15, 27], diluted from
would range from being greater than the particulate fraction concentrate [8, 16] or fresh frozen [18] has been shown to
to equivalent to the grapefruit juice. Felodipine AUC were interact with felodipine. However, the magnitude of the
higher with supernatant fraction and particulate fraction interaction may differ among brands or even lots of juice
compared to water demonstrating that both fractions depending upon the amount of active ingredient(s) present.
contained the active substance(s). However, the supernatant Although double-strength grapefruit juice has been studied
fraction had lower felodipine AUC than the particulate in some investigations [12, 17], it is evident that a single
fraction. It was concluded that naringin and 6∞,7∞- glass (200–250 ml) of regular-strength grapefruit juice can
dihydroxybergamottin are not the major active ingredients produce a several-fold increase in felodipine AUC and Cmax
although they may contribute to the interaction. Recently, [5, 8, 14–18]. This action of a commonly used portion of
other furanocoumarins isolated from grapefruit juice were grapefruit juice highlights its practical importance.
reported to inhibit in vitro human CYP3A [102, 104]. Administration-related factors appear to affect the inter-
However, a final decision on their importance to the action. A marked response may occur with grapefruit juice
interaction must await results from in vivo testing in humans. and the initial drug dose and this could be greater following
previous regular juice consumption. However, the cause
could be erroneously attributed to inherent variation in
Therapeutic considerations
normal drug effect among patients and overlooked as an
The clinical importance of any drug interaction depends on interaction by patient, pharmacist or physician. It might be
several factors. Of initial concern is the extent of change in better recognized clinically in patients stabilized on a
drug pharmacokinetics. If there is a doubling or more of particular dose of a medication when grapefruit juice is
plasma drug concentration by grapefruit juice it should alert added to the diet. Anecdotally, this has been observed with
the physician or pharmacist to the possibility of enhanced, felodipine in two patients with increased accessibility to
excessive or adverse drug effect. In the case of felodipine, fresh grapefruit juice either while on winter vacation in
doubling drug Cmax with grapefruit juice produced twice warmer climates or following ripening of grapefruits in a
the blood pressure reduction, heart rate increase and backyard tree ( personal communication). In contrast, a
frequency of vasodilatation-related adverse events in border- diminution of drug response may result following discontinu-
line hypertensive patients [12]. Other medications which ation of the juice.
have demonstrated at least a doubling of plasma drug
concentrations with grapefruit juice include dihydropyridines
Conclusions
with low oral bioavailability, terfenadine [57] and saquinavir
[73]. Furthermore, a lesser pharmacokinetic effect can be A single glass of grapefruit juice has the potential to augment
clinically important for a medication with a steep concen- the oral bioavailability and to enhance the beneficial or
tration (dose) response relationship or a narrow therapeutic adverse effects of a broad range of medications, even by
window so that even a modest increase of plasma drug juice consumed hours beforehand. Grapefruit juice acts by
concentration could be translated into augmented or adverse inhibiting presystemic drug metabolism mediated by CYP3A
effects. Thus, increases in plasma drug concentrations of isoforms in the small bowel. The interaction appears
cyclosporin [65–71], midazolam [62], triazolam [63] and particularly relevant for medications with at least a doubling
verapamil [34] by grapefruit juice also appear pertinent. of plasma drug concentration or with a steep concentration-
Patient susceptibility is relevant to the interaction. response relationship or a narrow therapeutic index. Patients
Individuals that are highly dependent upon intestinal that appear particularly susceptible have high small bowel
CYP3A4 activity for presystemic drug elimination, and CYP3A4 content, hepatic insufficiency or a pre-existing
perhaps especially patients with hepatic insufficiency, appear medical condition which predisposes to enhanced, excessive
particularly sensitive for an interaction with grapefruit juice. or abnormal drug effects. Since grocers do not take a drug
Dihydropyridines like felodipine produce an antihypertensive history, physicians, pharmacists and other health professionals
effect not only dependent upon plasma drug concentration should educate patients about consumption of grapefruit
[105] but also on pretreatment blood pressure with the juice with medications.
greatest drop in blood pressure occurring in patients with Isolation of the active ingredient(s) may lead to identifi-
the highest pretreatment pressure [106]. This interaction cation of other foods producing this interaction or to its
appears particularly important for drugs of this class since incorporation into pharmaceutical formulations. Further
the greater mortality of post-infarction patients and the research is required to understand the interaction better

106 © 1998 Blackwell Science Ltd Br J Clin Pharmacol, 46, 101–110

 Grapefruit juice—drug interactions

during routine grapefruit juice consumption, at amounts pharmacokinetics and pharmacodynamics of felodipine in
considered safe for administration with drugs and with healthy subjects. Eur J Clin Pharmacol 1995; 49: 61–67.
different patient populations. Nevertheless, the serendipitous 16 Bailey DG, Arnold JMO, Bend JR, Tran LT, Spence JD.
observation of increased plasma felodipine concentrations by Grapefruit juice-felodipine interaction: reproducibility and
characterization with the extended release drug formulation.
grapefruit juice has provided fundamental new knowledge
Br J Clin Pharmacol 1995; 40: 135–140.
to improve pharmacotherapy and to stimulate research.
17 Edgar B, Bailey DG, Bergstrand R, Johnsson G, Regardh
CG. Acute effects of drinking grapefruit juice on the
This work was supported by grants from the Medical pharmacokinetics and pharmacodyanmics of felodipine—and
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