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Pakistan Journal of Pharmaceutical Sciences

Vol. 18, No.4, October 2005, pp.45-57

REVIEW
GRAPE FRUIT JUICE – DRUG INTERACTIONS

M. SAEED ARAYNE, NAJMA SULTANA* AND ZAKIA BIBI

Department of Chemistry, University of Karachi, Karachi-75270, Email: [email protected]
*Research Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, University of Karachi

Grapefruit juice can markedly augment oral drug bioavailability was originally 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 24h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. Clinically
relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam,
triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole (Guo et al., 2000).
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 metabolism
mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most
dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur
with lovastatin, cisapride and astemizole. The importance of these interactions 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’-dihydroxybergamottin, as being active
ingredients. A recent investigation indicated that neither of these substances made a major contribution to grapefruit
juice-drug interactions in humans (Guo et al., 2000).

Keywords: Grape fruit, interaction, cytochrome P450 3A4, CYP 3A4, 6', 7’-dihydroxybergamottin, flavonoid,
naringin, dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam, verapamil, lovastatin,
cisapride and astemizole.
46 Grape fruit juice – Drug interactions.

INTRODUCTION that recovery depends on regeneration of enteric CYP3A

enzyme. This study evaluated the time course of CYP3A
The opportunity for a food-drug interaction is an everyday inhibition and recovery after a single exposure to grapefruit
occurrence, which can be particularly important when total juice. Midazolam benzodiazepine derivative was used as an
drug absorption is altered. Recently, a chance observation in vivo probe for human CYP3A activity (Streetman et al.,
led to the finding that grapefruit juice could markedly 2000), which is metabolized exclusively by CYP3A
increase the oral bioavailability of a number of medications isoforms (Kronbach et al., 1989; Gorski et al., 1994; Ghosal
(Bailey et al., 1994). This article retraces discovery of this et al., 1996; Perloff et al., 2000 and Von Moltke et al.,
novel interaction and reviews the mechanism of action, 1996). After oral dosing, midazolam undergoes extensive
summaries studied and predicted medications for an presystemic extraction by a combination of hepatic and
interaction, discusses possible active ingredient in the juice enteric CYP3A, with oral bioavailability averaging
and considers clinical implications. approximately 30% (Tsunoda et al., 1999; Thummel et al.,
1996 and Gorski et al., 1998). Systemic exposure to
In 1989 it was reported that coadministration of grapefruit midazolam after oral administration is increased by 1.5- to
juice with the calcium channel antagonist felodipine resulted 3-fold after coadministration of grapefruit juice (Rogers et
in a large increase in serum felodipine concentrations, as al., 1999; Kupferschmidt et al., 1995 and Andersen et al.,
well as an enhancement of the pharmacodynamic effects of 2000). These authors also evaluated the capacity of 6′7′-
the drug (Bailey et al., 1989). Subsequent work (Kane and dihydroxybergamottin (DHB) and of bergamottin, two
Lipsky et al., 2000; Ameer and Weintraub et al., 1997; furanocoumarin derivatives present in grapefruit juice, to
Greenblatt et al., 2001; Bailey et al., 1998 and Fuhr., 1998) inhibit the activity of human CYP3A in vitro, using
has established that furanocoumarin derivatives and other midazolam (the same probe compound as was used in the
substances present in commercially available grapefruit clinical study), as well as triazolam, used as CYP3A index
juice have the capacity to inhibit the activity of human substrates.
cytochrome P450 (CYP) 3A enzymes present in
gastrointestinal tract mucosal cells (Edwards et al., 1996; In vitro drug interaction studies of grape fruit juice with
Bailey et al., 2000; Fukuda et al., Guo et al., 2000a; Ohnishi cephalosporins (cefazolin, and ceftizoxime) and quinolones
et al., 2000; Lown et al., 1997; Bailey et al., 1998a; (ciprofloxacin and ofloxacin), the contents of grape fruit
Edwards et al., 1999; Schmiedlin-Ren et al., 1997; juice were found to form charge transfer compleses under
Tassaneeyakul et al., 2000; Guo et al., 2000a; Fukuda et al., conditions of the reactions. Moreover while all the ascorbic
1997 and Iyer et al., 1998). The pattern of inhibition is both acid present in fruit juice reacted with both cephalosporins
reversible (competitive or noncompetitive) and irreversible and quinolones. In order to avoid such drug interactions, it
(mechanism-based). The outcome of the interaction is a is recommended not to co administer these drugs with grape
reduction in presystemic extraction of a number of orally fruit juice.
administered medications, causing increased bioavailability,
higher plasma levels, and possibly enhancement of Discovery
pharmacodynamic effects. Drug interactions with grapefruit Originally, a study was designed to test for an interaction
juice will occur only if the drug in question is a substrate for between ethanol and the dihydropyridine calcium channel
human CYP3A, the drug has low oral bioavailability as a antagonist, felodipine (Bailey et al., 1989) an analogue of
result of presystemic extraction, enteric CYP3A contributes nifedipine. Grapefruit juice was chosen to mask the taste of
significantly to presystemic extraction, and the individual the ethanol following an assessment of every juice in a
subject expresses significant quantities of enteric CYP3A. home refrigerator one Saturday evening. White grapefruit
Grapefruit juice produces less CYP3A inhibition as juice, particularly double-strength juice (single dilution of
compared with highly potent inhibitors such as ketoconazole frozen concentrate), was the most effective. The
and ritonavir (Venkatakrishnan et al and 2000; Greenblatt et combination of a non-intoxicating dose of ethanol and
al., 2000). It will not alter the clearance of drugs felodipine resulted in lower standing blood pressure and a
metabolized by other CYP isoforms and except at very high high frequency of orthostatic hypotension compared with
dosages (Lilja et al., 2000), will not influence the activity of felodipine alone in patients with untreated borderline
hepatic CYP3A. Medications given by any route of hypertension (Bailey et al., 1989) Although plasma
administration other than oral are not affected by grapefruit felodipine concentrations were not different between
juice, even if they are substrates for CYP3A. While the treatments, they were several-fold higher than observed in
capacity of grapefruit juice to inhibit human enteric CYP3A other pharmacokinetic investigations with the same dose of
activity is well established, the time course of recovery has drug. A systematic examination for obvious possible causes,
received less attention, and the data available are conflicting such as incorrect dose or drug assay problems, did not
(Lilja et al., 2000; Takanaga et al., 2000a and Lundahl et al., resolve this discrepancy and eventually resulted in a pilot
1995). As inhibition of CYP3A by grapefruit juice has a project in a single volunteer to judge the role of the juice.
mechanism-based (irreversible) component, it is possible
M. Saeed Arayne et al 47

Plasma felodipine concentrations were more than five-fold least 10-fold among individuals and appears to be regulated
greater with grapefruit juice compared with water (fig. 1). independently of the other (Lown et al., 1994).

Grapefruit juice effects

The first report of this interaction revealed that grapefruit
juice, but not orange juice, tripled mean plasma felodipine
AUC compared to water in borderline hypertensive patients
(Bailey et al., 1991). Blood pressure reduction, heart rate
increase and frequency of vasodilatation-related adverse
events were also greater. Grapefruit juice markedly elevated
plasma peak felodipine concentration (Cmax) but did not alter
systemic felodipine elimination half-life (t 1/2) (Bailey et al.,
1991). Since grapefruit juice did not change intravenous
felodipine pharmacokinetics (Lundahl et al., 1997), it
indicates that the interaction with grapefruit juice resulted
from inhibition of presystemic drug metabolism.

Fig. 1: Plasma felodipine concentration-time profile from Grapefruit juice reduced dehydrofelodipine/felodipine AUC
the pilot study in which the effect of grapefruit juice. ratio and increased absolute dehydrofelodipine AUC (Bailey
et al., 1991 and Bailey et al., 1994). The decrease in the
Felodipine disposition and metabolism AUC ratio was compatible with inhibition of the primary
Felodipine has been the most extensively studied probe for metabolic pathway. The absolute increase in dehydro-
grapefruit juice-drug interactions. Normally, felodipine is felodipine AUC indicated that a subsequent metabolic
completely absorbed from the gastrointestinal tract pathway might also be inhibited and this was supported by
following oral administration (Edgar et al., 1985) however, measurements showing that the M3 metabolite AUC was
it undergoes high presystemic (first-pass) metabolism reduced (Bailey et al., 1996). Thus, grapefruit juice
resulting in low absolute bioavailability averaging 15% appeared to inhibit CYP3A4, an important isozyme of
(Edgar et al., 1985) but ranging from 4% to 36% among cytochrome P450 since it oxidizes a broad range of drugs
individuals (Blychert et al., 1991). Both the gut wall and the and xenobiotics (Guengerich 1994), with predominant and
liver appear responsible for presystemic felodipine perhaps exclusive action on presystemic drug elimination.
elimination (Lundahl et al., 1997). Felodipine has a single
primary metabolite, dehydrofelodipine (Regardh et al., Recently, the effect of grapefruit juice on drug metabolizing
1990), generated by cytochrome P450 3A4 CYP3A4; fig.2 enzymes of the small bowel and liver was reported in an in
(Guengerich et al., 1991). vivo investigation in humans (Lown et al., 1997). 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 breathe
test, and colon CYP3A5 protein content were not altered.
Moreover, 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 small bowel CYP3A4 can be markedly reduced
4 h after a single glass of juice. Consequently, it was
concluded that grapefruit juice acted by selectively
inhibiting CYP3A isozymes of the small bowel to cause
greater felodipine oral bioavailability.
Fig. 2: Pathways of felodipine metabolism.
Decreased expression of CYP3A isoforms by grapefruit
Dehydrofelodipine is inactive and oxidized by two juice implied that the interaction was not simple competition
secondary pathways. The major secondary metabolite, M3, for substrate metabolism. Since small bowel CYP3A4
is also produced by CYP3A4 (Bailey et al., 1996). Apical mRNA was not changed (Lown et al., 1997), grapefruit
enterocytes of the small bowel and hepatocytes of the liver juice likely decreased CYP3A4 protein content by a post-
both contain CYP3A4 (Kolars et al., 1992; Waziers et al., transcriptional mechanism, possibly involving accelerated
1990). The content of CYP3A4 in both tissues ranges at CYP3A4 degradation through mechanism-based enzyme
48 Grape fruit juice – Drug interactions.

inhibition. Thus, the return of CYP3A4 activity would which have similar pathways of metabolism (Regardh et al.,
require de novo enzyme synthesis, which could result in 1990) , but vary markedly in absolute oral bioavailability
prolonged effect of grapefruit juice. dependent upon extent of presystemic drug elimination
(Abernethy and Schwartz, 1988).
The duration of activity of grapefruit juice has also been
studied. In one study, consumption of a single glass Based on the previous discussion, it would be expected that
(200 ml) of juice at various time intervals before felodipine a dihydropyridine with low inherent oral bioavailability
showed that the extent of increase in felodipine AUC and would have a greater magnitude of the interaction with
Cmax was maximal between simultaneous and 4 h previous grapefruit juice than with a dihydropyridine with normally
juice administration with drug (Undahl et al., 1995). Then, high oral bioavailability (Bailey et al., 1993) and
the magnitude of the interaction declined slowly with amlodipine (Josefsson et al., 1996) are examples of
increasing time interval between grapefruit juice and dihydropyridines with very low and very high innate oral
felodipine administration. The half-life of effect of bioavailability, respectively. Mean (range) drug Cmax for
grapefruit juice was estimated at 12 h. Higher felodipine nisoldipine was 406% (107% -- 836%) (Bailey et al., 1993)
Cmax was still evident when grapefruit juice was consumed and for amlodipine was 115% (79% – 165%) (Josefsson et
24 h before felodipine. In another investigation, the effect of al., 1996) with grapefruit juice compared with water. Thus,
routine grapefruit juice consumption was evaluated (Lown nisoldipine did have a much greater fold increase of plasma
et al., 1997). One glass (250 ml) of grapefruit juice drug concentrations compared with amlodipine. Further-
augmented mean felodipine AUC and Cmax to 267% and more, inter individual variability of the interaction was
345%, respectively, of that compared with water. Grapefruit larger for nisoldipine which highlights the unpredictability
juice three times daily with meals for 5 days further of the interaction among individuals for dihydropyridines
increased felodipine AUC and Cmax to 345% and 538% of with low oral bioavailability.
that compared with water showing a cumulative effect of the
juice. All dihydropyridines, apart from nifedipine, have a chiral
centre with activity primarily residing with a particular
The magnitude of the interaction was highly variable among enantiomer (Regardh et al., 1990). The relevance of an
individuals ranging from no change to six-fold greater interaction with grapefruit juice then depends mostly on the
plasma felodipine AUC and Cmax with grapefruit juice magnitude of increase of the more active enantiomer. For
compared with water under single dose conditions (Bailey et nitrendipine, the S-enantiomer possesses the activity (Mikus
al., 1994; Bailey et al., 1996; Lown et al., 1997 and Bailey et al., 1989 and Eltze et al., 1990). Grapefruit juice
et al., 1995). However, it was reproducible within produced proportional enhancement of both enantiomers
individuals following repeat testing and thus, dependent on indicating that the increase in plasma total nitrendipine
factors inherent to the individual (Bailey et al., 1995). concentration was predictive of the pharmacodynamic
Grapefruit juice reduced small bowel CYP3A4 content extent of interaction (Soons et al., 1991). For nicardipine,
contingent upon pretreatment levels (Lown et al., 1997). the S-enantiomer has one-third the activity of the R-
Individuals with the highest small bowel CYP3A4 content enantiomer (Takenaka et al., 1982). Grapefruit juice
before grapefruit juice had the largest reduction in CYP3A4 augmented S-nicardipine AUC and Cmax by 1.5 and 1.2 fold
and highest increase in felodipine Cmax with grapefruit juice. more than R-nicardipine demonstrating that the effect on
Consequently, individual disparity in the magnitude of plasma total nicardipine concentration may slightly
interaction with grapefruit juice appears at least partially overestimate associated clinical consequences (Uno et al.,
explained by innate differences in baseline small bowel 1997). The S-enantiomer of non-dihydropyridine calcium
CYP3A4 protein content. channel antagonist, verapamil, has at least 10 times the
dromotropic activity compared with the R-enantiomer
Interactions with other drugs (Echizen et al., 1988). Grapefruit juice produced less than a
Most medications investigated for an interaction with doubling of mean plasma total verapamil AUC and Cmax
grapefruit juice are substrates for CYP3A4. The most (Fuhr et al., 1994). However, first-degree heart block (PR
extensively studied are the dihydropyridine calcium channel interval >240 ms) was observed in only subjects (4 of 24)
antagonists. In addition to felodipine (Lundahl et al., 1997; who received verapamil with grapefruit juice. Although
Bailey et al., 1996; Bailey et al., 1991; Lown et al., 1997; inter-subject variation of the interaction was not reported,
Undahl J et al., 1995; Bailey et al., 1995; Edgar et al., 1992 grapefruit juice may preferentially augment S-verapamil and
and Bailey et al., 1993a), these include nisoldipine (Bailey et thus, the increase in plasma total verapamil concentrations
al., 1993a), nimodipine (Fuhr et al., 1994a), nicardipine would underestimate the importance of the interaction.
(Uno et al 1997), nitrendipine (Soons et al 1991 and Bailey
et al., 1992), nifedipine (Bailey et al., 1991; Rashid et al The non-sedating antihistamine, terfenadine, undergoes
1993; Rashid et al., 1995 and Sigush et al., 1994), and nearly complete presystemic elimination mediated by
amlodipine (Josefsson et al., 1996 and Vincent et al., 1997), CYP3A4 (Garteiz et al., 1982 and Yun et al., 1993) and is
M. Saeed Arayne et al 49

often not detected in plasma. One of the primary solubility and diffusion; characteristics; more recent work
metabolites, terfenadine carboxylate, accounts for the has supported presystemic cyclosporin metabolism as a
activity (Yun et al., 1993). Terfenadine, like quinidine, is a factor (Kolars et al., 1991). In two studies of healthy
potent blocker of myocyte delayed rectifier potassium volunteers, grapefruit juice produced mean oral cyclosporin
current whereas terfenadine carboxylate is devoid of this AUCs that were 162% and 143% of that with water
effect (Woosley et al., 1993; Yang et al., 1995 and Rampe (Ducharme et al., 1995 and Yee et al., 1995). Orange juice
et al., 1993). Plasma terfenadine concentrations can be did not augment cyclosporin AUC (Yee et al., 1995).
measured with overdose, liver disease or inhibition of Several studies were conducted in medically stable renal
CYP3A4 metabolism by concomitant administration of transplant patients (Ducharme et al., 1993; Herlitz et al
ketoconazole, erythromycin or itraconazole and are 1993; Hollander et al., 1995; Proppe et al., 1995 and Min et
associated with prolongation of the QTc interval and al., 1996). Grapefruit juice was given with the patient's
development of a serious ventricular tachyarrhythmia, usual oral dose of cyclosporin to achieve steady state. The
torsades de pointes (Davies et al., 1989; Monahan et al., effect of grapefruit juice on cyclosporin pharmacokinetics
1990; Matthews et al., 1991; Zimmermann et al., 1992; varied among studies. Plasma cyclosporin AUC (Herlitz et
Honig et al., 1993; Pratt et al., 1994; Crane and Shih et al., al 1993; Proppe et al., 1995 and Min et al., 1996) and
1993; Pohjola-Sintonen et al., 1993; Honig et al., 1993; trough concentration (Herlitz et al 1993 and Proppe et al.,
Honig et al., 1992; Paris et al., 1994; Koh et al., 1994 and 1995), which is commonly used during therapeutic drug
Kamisako et al., 1995). Approximately 125 deaths linked to monitoring, was augmented in some investigations. The
terfenadine have been reported (Flockhart, 1996). largest mean interaction was a cyclosporin AUC and trough
Controlled clinical investigations have shown that grapefruit concentration with grapefruit juice that were 134% and
juice augmented plasma terfenadine concentrations (Benton 177%, respectively, of that compared with water (Proppe et
et al., 1996; Honig et al., 1996; Rau et al., 1997 and al., 1995). There was more than a tripling in plasma trough
Clifford et al., 1997). A small increase in the QTc interval cyclosporin concentration in at least one patient, which
was demonstrated (Benton et al., 1996 and Honig et al., undoubtedly is clinically important (Min et al., 1996). As
1996). The magnitude of the interaction was similar to that cyclosporin is very expensive, administration with
produced by itraconazole or erythromycin (Rau et al., grapefruit juice has been suggested as a technique to
1997). A fatality has been attributed to terfenadine toxicity decrease drug costs (Yee et al., 1995). However, the
after consuming the drug with grapefruit juice (Spence, magnitude of the effect is variable among patients and the
1997). Since there appears to be little benefit from taking constancy of the interaction with repeat dosing has not been
grapefruit juice with terfenadine and there is the potential documented. Thus, concurrent administration of grapefruit
for a serious adverse interaction, regardless of the frequency juice cannot presently be recommended as a therapeutic
of occurrence, it seems wise to advice against grapefruit strategy for such patients (Johnston and Holt, 1995). The
juice consumption during therapy with terfenadine. anti-AIDS drug, saquinavir, belongs to a new class of agents
known as protease inhibitors; its very low bioavailability is
Midazolam and triazolam are two ultra-short acting in part due to presystemic metabolism by CYP3A4. A glass
benzodiazepine hypnotics with high presystemic drug of regular-strength grapefruit juice augmented saquinavir
metabolism. For midazolam, a substantial portion of AUC to 150% of that with water in HIV-negative volunteers
presystemic metabolism appears to occur in the small bowel (James; 1995). Double-strength grapefruit juice enhanced
(Thummel et al., 1996 and Paine et al., 1996) and the major saquinavir AUC to 220%, since saquinavir has a wide
primary metabolite, 1'-hydroxymidazolam, is generated by therapeutic window; concomitant administration of grape-
CYP3A4 (Kronbach et al., 1989). Grapefruit juice increased fruit juice has been suggested as a strategy to increase
mean midazolam AUC and Cmax by an estimated 41% saquinavir bioavailability. Although the magnitude of the
selective decrease of prehepatic midazolam metabolism interaction may be variable among patients, there appears to
(Kupferschmidt et al., 1995). Psychometric tests showed be only the potential for enhanced therapeutic benefit.
greater patient impairment when oral midazolam was
administered with grapefruit juice compared with water. Grapefruit juice did not interact with a number of other
Similarly, grapefruit juice augmented triazolam AUC and medications; these include prednisone (Hollander et al.,
Cmax to produce enhanced drowsiness (Hukkinen et al., 1995), acenocoumarol (Van Rooij et al., 1993), quinidine
1995). (Min et al., 1994) and theophylline (Fuhr et al., 1995). This
is not unexpected since these drugs already have high or
Cyclosporin is the cornerstone of immunosuppression almost complete oral bioavailability. Prednisone and
therapy following transplantation. Plasma cyclosporin theophylline are also not substrates for CYP3A4. However,
concentrations must be maintained within a narrow range to grapefruit juice did prolong the systemic elimination half-
achieve adequate immunosuppression without nephro- life of caffeine, a probe for CYP1A2 activity, and
toxicity. However, cyclosporin possesses low and variable theophylline is metabolized by CYP1A2 (Fuhr et al., 1993).
oral bioavailability, which has been attributed to poor drug This discrepancy for theophylline may be resolved by a
50 Grape fruit juice – Drug interactions.

recent report suggesting that grapefruit juice decreased grapefruit juice might be also used commercially to dose
caffeine elimination by inhibition of flavin-containing orally drugs that are currently active only by the intravenous
monooxygenase, a P450 independent system that does not route because of complete presystemic metabolism
appear to metabolize theophylline (Chung et al., 1997). involving CYP3A4 or to produce higher and more
Other medications not showing an interaction with dependable drug bioavailability and clinical response among
grapefruit juice include propafenone (Munoz et al., 1997), or within individuals (Bailey et al., 1994). In addition,
diltiazem (Sigusch et al., 1994), ethinyloestradiol (Weber et because hepatic CYP3A4 activity does not appear to be
al., 1996) and 17-β-oestradiol (Schubert et al., 1994). altered by grapefruit juice (Lown et al., 1997), a major
Although they undergo presystemic metabolism, it appears mechanism for systemic drug inactivation is not
that pathways do not mediate a substantial portion by jeopardized. However, the persistence of hepatic CYP3A4
CYP3A4 (Schubert et al., 1994). activity means that it would not likely be possible to
produce complete oral drug bioavailability.
Drugs predicted to interact with grapefruit juice
The HMG-CoA reductase inhibitor, lovastatin, has been Flavonoids can inhibit drug oxidative metabolism (Buening
reported to produce serious adverse skeletal muscle effect, et al., 1981). Naringin (Fig.3) is the most prevalent
rhabdomyolysis, when administered with drugs that inhibit flavonoid in grapefruit juice attaining relatively high
CYP3A4 including itraconazole (Lees, 1995), erythromycin concentrations (1 mmol l-1) and is absent from orange juice
(Spach et al., 1991) and cyclosporin (Norman et al., 1988). (Kuhnau, 1976), which did not produce the interaction
Lovastatin is a prodrug, which normally undergoes (Bailey et al., 1991 and Yee et al., 1995). Naringin inhibited
extensive presystemic elimination (Neuvonen and Jalava; in vitro felodipine and nifedipine metabolism but was much
1996). Less than 5% of lovastatin is hydrolyzed to the less potent than its aglycone, naringenin (Meier et al., 1995;
pharmacologically active metabolite, lovastatin acid, with Deslypere and Vermeulen, 1991). Although naringenin is
the majority biotransformed by other primary routes not normally present in grapefruit juice (Kuhnau, 1976),
mediated by CYP3A4 (Wang et al., 1991). Lovastatin and oral administration of grapefruit juice resulted in renal
active metabolite AUCs were increased more than twenty- excretion of naringenin conjugates demonstrating in vivo
fold when administered with itraconazole suggesting the formation of this potentially active species (Guengerich and
adverse effect has a pharmacokinetic basis (Neuvonen and Kim, 1990 and Miniscalco et al., 1992) (Fuhr and Kummert,
Jalava, 1996). Rhabdomyolysis has also been reported with 1995). Also, naringenin was not detected in plasma and the
simvastatin (Meier et al., 1995; Vermeulen., 1991; total amount recovered in urine represented only a small
Rosenberg et al., 1995 and Hino et al., 1996). Thus, a percentage of the oral naringin dose in the juice (Fuhr and
clinically important interaction may occur between Kummert, 1995), suggesting that naringenin has low
grapefruit juice and lovastatin and possibly other HMG- systemic availability which is consistent with inhibition of
CoA reductase inhibitors. drug metabolism localized to the small bowel. Nevertheless,
commercially available pure naringenin, administered in the
Prolonged QT interval, torsade de pointes and fatal same amount as found in grapefruit juice, produced little or
arrhythmia have been reported with the gastrointestinal no increase in the plasma concentrations of felodipine
prokinetic agent, cisapride (Wysowsk and Bacsanyi, 1996). (Bailey et al., 1993), or nisoldipine (Bailey et al., 1993a).
Adverse events occurred in conditions where plasma
cisapride concentrations were elevated, particularly with
concomitant administration of medications that inhibit
CYP3A4. Cisapride normally undergoes presystemic
metabolism by CYP3A4 resulting in a 40-50% absolute oral
bioavailability (Bedford and Rowbotham, 1996). Torsade de
pointes have also been observed with the non-sedating
antihistamine, astemizole, when administered with
ketoconazole (Tsai et al., 1997). Astemizole has high
presystemic elimination by three major metabolic routes to
produce an estimated 3% oral bioavailability (Krstenansky
and Cluxton, 19987). Unless medical condition warrants
their use, it might be prudent to avoid the combination of
grapefruit juice with cisapride or astemizole.

Active ingredient in grapefruit juice

Identification of the active ingredient in grapefruit juice
would permit evaluation of this type of interaction with Fig. 3: Chemical structures of naringin and 6', 7’-
other foods. The apparently non-toxic active ingredient in dihydroxybergamottin.
M. Saeed Arayne et al 51

A furanocoumarin, 6', 7’-dihydroxybergamottin, has been plasma drug concentrations with grapefruit juice include
recently proposed as an active ingredient in grapefruit juice dihydropyridines with low oral bioavailability, terfenadine
(Edwards et al., 1996). It and a related dimer caused a dose- (Clifford et al., 1997) and saquinavir (James; 1995).
dependent fall in CYP3A4 catalytic activity and Furthermore, a lesser pharmacokinetic effect can be
immunoreactive CYP3A4 protein concentration in a Caco-2 clinically important for a medication with a steep
cell culture model of human intestinal epithelium concentration (dose) response relationship or a narrow
(Schmiedlin-Ren et al., 1997). The concentration of 6', 7’- therapeutic window so that even a modest increase of
dihydroxybergamottin in grapefruit juice exceeded the IC50 plasma drug concentration could be translated into
for loss of CYP3A4 activity. CYP1A1 and CYP2D6 protein augmented or adverse effects. Thus, increases in plasma
content were not affected. 6', 7’-dihydroxybergamottin acted drug concentrations of cyclosporin, midazolam
initially by competitive inhibition followed by mechanism- (Kupferschmidt et al., 1995), triazolam (Hukkinen et al.,
based inactivation of recombinant CYP3A4 consistent with 1995) and verapamil (Fuhr et al., 1994) by grapefruit juice
the in vivo effects observed in humans. also appear pertinent. Patient susceptibility is relevant to the
interaction, individuals that are highly dependent upon
Recently a study was reported that tested the hypothesis that intestinal CYP3A4 activity for presystemic drug
naringin and/or 6',7’-dihydroxybergamottin in grapefruit elimination, and perhaps especially patients with hepatic
juice are primarily responsible for the interaction with insufficiency, appear particularly sensitive for an interaction
felodipine in humans (Bailey et al., 1993a). The approach with grapefruit juice. Dihydropyridines like felodipine
was to separate grapefruit juice by centrifugation and produce an antihypertensive effect not only dependent upon
ultrafiltration into supernatant and particulate fractions. plasma drug concentration (Blychert et al., 1990) but also
Then, the effect on oral felodipine pharmacokinetics of on pretreatment blood pressure with the greatest drop in
these fractions, of grapefruit juice containing a comparable blood pressure occurring in patients with the highest
amount of both fractions and of water were compared in pretreatment pressure (Leenen et al., 1988). This interaction
healthy male volunteers. Because the amounts of naringin appears particularly important for drugs of this class since
and 6',7’-dihydroxybergamottin were found to be greater in the greater mortality of post-infarction patients and the
the supernatant fraction (148 mg and 1.85 mg, respectively) suggestion of adverse outcome for hypertensives treated
than the particulate fraction (7 mg and 0.60 mg, with immediate release dihydropyridines would argue that a
respectively), it was postulated that the activity of the rapid increase in plasma dihydropyridine concentration by
supernatant fraction would range from being greater than grapefruit juice, even with the extended release formulation
the particulate fraction to equivalent to the grapefruit juice. (Lundahl et al., 1997; Bailey et al., 1996; Lown et al., 1997;
Felodipine AUC was higher with supernatant fraction and Undahl et al., 1995 and Bailey et al., 1995, may put these
particulate fraction compared to water demonstrating that patients at risk of ischaemic complications (Furberg and
both fractions contained the active substance. However, the Nifedipine, 1995; Kloner, 1995; Yusuf., 1995 and Waters,
supernatant fraction had lower felodipine AUC than the 1991). Also, terfenadine with grapefruit juice may have
particulate fraction. It was concluded that naringenin and 6', increased chance of producing torsades de pointes in
7’-dihydroxybergamottin are not the major active individuals with pre-existing prolonged QT interval.
ingredients although they may contribute to the interaction.
Recently, other furanocoumarins isolated from grapefruit Grapefruit juice type and amount are also important
juice were reported to inhibit in vitro human CYP3A considerations. Commercial white grapefruit juice from
(Schmiedlin-Ren et al., 1997 and Fukuda et al., 1997). frozen concentrate (Lundahl et al., 1997; Bailey et al., 1991;
However, a final decision on their importance to the Lown et al., 1997; Undahl et al., 1995 and Josefsson et al.,
interaction must await results from in vivo testing in 1996), diluted from concentrate (Bailey et al., 1996 and
humans. (Bailey et al., 1994) or fresh frozen (Bailey et al., 1993) has
been shown to interact with felodipine. However, the
Therapeutic considerations magnitude of the interaction may differ among brands or
The clinical importance of any drug interaction depends on even lots of juice depending upon the amount of active
several factors. Of initial concern is the extent of change in ingredient present. Although double-strength grapefruit
drug pharmacokinetics. If there is a doubling or more of juice has been studied in some investigations (Bailey et al.,
plasma drug concentration by grapefruit juice it should alert 1991; Josefsson et al., 1996), it is evident that a single glass
the physician or pharmacist to the possibility of enhanced, (200-250 ml) of regular-strength grapefruit juice can
excessive or adverse drug effect. In the case of felodipine, produce a several-fold increase in felodipine AUC and C max
doubling drug Cmax with grapefruit juice produced twice the (Lundahl et al., 1997; Bailey et al., 1996; Lown et al., 1997;
blood pressure reduction, heart rate increase and frequency Undahl et al., 1995; Bailey et al., 1995; Edgar et al., 1992
of vasodilatation-related adverse events in borderline and Bailey et al., 1993). This action of a commonly used
hypertensive patients (Bailey et al., 1991). Other portion of grapefruit juice highlights its practical
medications which have demonstrated at least a doubling of importance.
52 Grape fruit juice – Drug interactions.

Administration-related factors appear to affect the Andersen V, Pedersen N, Larsen NE, Sonne J and Larsen S
interaction. A marked response may occur with grapefruit (2002). Intestinal first pass metabolism of midazolam in
juice and the initial drug dose and this could be greater liver cirrhosis-effect of grapefruit juice. Br J. Clin.
following previous regular juice consumption. However, the Pharmacol., 54: 120-124.
cause could be erroneously attributed to inherent variation Bailey DG, Arnold JMO, Bend JR, Tran LT, Spence JD
in normal drug effect among patients and overlooked as an (1995). Grapefruit juice-felodipine interaction: reproduce-
interaction by patient, pharmacist or physician. It might be bility and characterization with the extended release drug
better recognized clinically in patients stabilized on a formulation. Br J. Clin. Pharmacol., 40: 135-140.
particular dose of a medication when grapefruit juice is Bailey DG, Arnold JMO, Munoz C and Spence JD (1993).
added to the diet. Anecdotally, this has been observed with Grapefruit juice-felodipine interaction: mechanism, pre-
felodipine in two patients with increased accessibility to dictability and effect of naringin. Clin. Pharmacol. Ther.,
fresh grapefruit juice either while on winter vacation in 53: 637-642.
warmer climates or following ripening of grapefruits in a Bailey DG, Arnold JMO and Spence JD (1994). Grapefruit
backyard tree (personal communication). In contrast, a juice and drugs: how significant is the interaction? Clin.
diminution of drug response may result following Pharmacokin., 26: 91-98.
discontinuation of the juice (Bailey et al., 1993). Bailey DG, Arnold JMO, Strong HA, Munoz C and
CONCLUSIONS Spence JD (1993a). Effect of grapefruit juice and naringin
on nisoldipine pharmacokinetics. Clin. Pharmacol. Ther.,
A single glass of grapefruit juice has the potential to 54: 589-594.
augment the oral bioavailability and to enhance the Bailey DG, Bend JR, Arnold JMO, Tran LT and Spence JD
beneficial or adverse effects of a broad range of (1996). Erythromycin-felodipine interaction: magnitude,
medications, even by juice consumed hours beforehand. mechanism, and comparison with grapefruit juice. Clin.
Grapefruit juice acts by inhibiting presystemic drug Pharmacol. Ther., 10: 25-33.
metabolism mediated by CYP3A isoforms in the small Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ
bowel. The interaction appears particularly relevant for and Bend JR (2000). Grapefruit-felodipine interaction:
medications with at least a doubling of plasma drug effect of unprocessed fruit and probable active ingredients.
concentration or with a steep concentration-response Clin. Pharmacol. Ther., 68: 468-477.
relationship or a narrow therapeutic index. Patients that Bailey DG, Malcolm J, Arnold O and Spence JD (1998).
appear particularly susceptible have high small bowel Grapefruit juice-drug interactions. Br. J. Clin. Pharmacol.,
CYP3A4 content, hepatic insufficiency or a pre-existing 46: 101-110.
medical condition, which predisposes to enhanced, Bailey DG, Munoz C, Arnold JMO, Strong HA and
excessive or abnormal drug effects. Since grocers do not Spence JD (1992). Grapefruit juice and naringin inter-
take a drug history, physicians, pharmacists and other health action with nitrendipine. (Abstract). Clin. Pharmacol.
professionals should educate patients about consumption of Ther., 51: 156.
grapefruit juice with medications. Bailey DG, Spence JD, Edgar B, Bayliff CD and Arnold JM
(1989). Ethanol enhances the hemodynamic effects of
Isolation of the active ingredient may lead to identification
felodipine. Clin. Invest. Med., 12: 357-362.
of other foods producing this interaction or to its
Bailey DG, Spence JD, Munoz C and Arnold JMO (1991).
incorporation into pharmaceutical formulations. Further
Interaction of citrus juices with felodipine and nifedipine.
research is required to understand the interaction better
during routine grapefruit juice consumption, at amounts Lancet., 337: 268-269.
considered safe for administration with drugs and with Bailey DG, Kreeft JH, Munoz C, Freeman DJ and Bend JR
different patient populations. Nevertheless, the serendipitous (1998a). Grapefruit juice-felodipine interaction: effect of
observation of increased plasma felodipine concentrations naringin and 6′, 7′-dihydroxybergamottin in humans. Clin.
by grapefruit juice has provided fundamental new Pharmacol. Ther., 64: 248-256.
knowledge to improve pharmacotherapy and to stimulate Bedford TA and Rowbotham DJ (1996). Cisapride: Drug
research. interactions of clinical significance. Drug Safety, 15: 167-
175.
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Pakistan Journal of Pharmaceutical Sciences

Vol. 18, No.4, October 2005, pp.57-61

REPORT
EFFECT OF MAGNESIUM AND ZINC ON ANTIMICROBIAL ACTIVITIES
OF SOME ANTIBIOTICS

FERDOUS KHAN, YOUNUS PATOARE*, PINKY KARIM*, ISRAT RAYHAN**,

MOHIUDDIN ABDUL QUADIR AND ABUL HASNAT
Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh
*Department of Pharmacy, University of Asia pacific, Dhanmondi, Dhaka, Bangladesh
**ISRT, University of Dhaka, Dhaka-1000, Bangladesh

Mg and Zn are essential elements in biological system. They are essential for enzymatic activity, maintaining three-
dimensional structure of proteins, for the synthesis of nucleic acids and proteins etc. Deficiency of Mg and Zn
causes different life threatening diseases. That is why the optimum level of Mg and Zn must be maintained for all
biological systems. The experiment was aimed to evaluate the effect of magnesium and zinc on the efficacy of
antibiotic agents against different microorganisms. It has been observed that the antibiotic activity of an antibiotic
agent increased significantly with concomitant use of Mg salt at a concentration ranging from 3-9 µg per antibiotic
disc. Similarly, Zn salt increased the activity of an antibiotic at a concentration ranging from 9-15 µg per antibiotic
disc. The experiment revealed that concomitant administration of antibiotic with Mg or Zn salt not only will
supplement the deficiency of these electrolytes but also will increase the activity of antibiotics against different
bacterial strains.

Keywords: Magnesium, zinc, antimicrobial activities, antibiotics.

INTRODUCTION is essential for almost all hormonal reactions in the body

because Mg is required for adenylate cyclase activity, which
Magnesium is one of the most abundant minerals in the is crucial for the transmission of extracellular hormonal
body and is a cofactor in over 300 enzymatic reactions. It is signals to intracellular targets (Boyd et al., 1983). Total
required for protein and nucleic acid synthesis, the cell body Mg content is approximately 1.15 mol of Mg, in an
cycle, cytoskeletal and mitochondrial integrity and the average 70 kg adult. Only the free ionized Mg fraction is
binding of substances to the plasma membrane. Magnesium biologically active (Wacker and Parisi, 1968).

Corresponding Author: Dr Abul Hasnat, Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, Dhaka
University, Dhaka-1000, Bangladesh, Email: [email protected]