REVIEW ON DRUG INTERACTIONS WITH

GRAPEFRUIT JUICE

Bachelor of Pharmacy

SUBMITTED BY Under the guidance of

Mr. TABREJ MUJAWAR
Mr.Rohit D. Usnale
M. Pharm.
Mr.Tushar K.Bhamre
Department of Pharmacology
Mr.Zahir Khan Gangamai college of Pharmacy,
Nagaon, Dist. Dhule
( 2010-2011)
 INDEX page no.

 1.Introduction 2

 2.History 3

 3.Objectives 3
 4.Role of pharmacist in patient communication 4

 5. Literature reviews 5
 6.Clinical significance of grapefruit drug interaction 7
 7.Active components of grapefruit juice 8
 8.Drug metabolism by CYPs 10
 9.Mechanism of action of grapefruit juice components 11
 10.Onset, duration and magnitude of effect of grapefruit
 juice on inhibition of CYP3A4 enzymes 13
 11.Grapefruit juice and drug interactions 16
 12.Management of Grapefruit-Drug Interactions 20
 13.Conclusion 23
1.Introduction1
 The grapefruit (Citrus paradisi) grows in clusters (like grapes) on a tree. Grapefruit
were initially discovered growing in the West Indies in the 1800s, and then brought
to the United States and Asian countries. Grapefruit is believed to have evolved from
the pummelo, a citrus fruit from the Rutaceae family (orange family), through
mutation or as a hybrid with the common orange. The grapefruit is larger than an
orange but smaller than most pummelos and can yield approximately 2/3 cup of
juice. There are two major types of grapefruit: white and pink/ ruby red.
 The discovery that grapefruit juice can increase the oral availability of some
medications was an accidental discovery made when grapefruit juice was used to
mask the taste of ethanol in a study involving the calcium channel blocker felodipine.
Since then, more different drugs have shown to enhance oral availability when
consumed with grapefruit juice. Most of the drugs affected by grapefruit juice have
poor and highly variable oral bioavailability. In addition, most of these drugs are
chiefly metabolized in the body by CYP3A4, an enzyme present in the liver and
intestine.
 The major effect of grapefruit juice appears to reduce “first-pass” metabolism by
reducing CYP3A4 activity. Because grapefruit juice does not generally affect the
systemic clearance of affected drugs, it appears that grapefruit juice selectively
reduces intestinal CYP3A4 activity while having little effect on liver CYP3A4.
Grapefruit juice has no effect on drug disposition after intravenous administration
and does not alter liver CYP3A4 activity.
2.History15
 In 1989 a pharmacological study evaluated the possibility of an
interaction between ethanol ingestion and medication with the
dihydropyridine calcium channel blocker - felodipine. Grapefruit juice was
used as a flavouring additive during the test. The results of study showed
several-fold increase of felodipine concentrations compared to results
obtained in other investigations of the drug. Additionally, there were lower
blood pressure readings and more adverse effects compared to the group of
subjects on felodipine alone. Further investigations revealed that grapefruit
juice strikingly elevated felodipine bioavailability and could influence its
other  pharmacokinetic and pharmacodynamic properties .
3.Objectives
 To identify the mechanism of grapefruit juice-drug interactions and drugs involved
with significant grapefruit-drug interactions
 To describe potential effects of grapefruit juice-drug interactions.
 Discuss medications that may be affected and degree of risk associated with common
interacting medications.
 To identify effective alternative medications that do not interact (for patients who do
not want to comply with dietary restrictions).
 To describe the pharmacist's role in communication the food-drug interaction issue to
patients and physicians.
 To effectively explain drug interaction risk factors and effective, alternative
medications for patients.
 4.Role of pharmacist in patient communication
Pharmacists play an important role in potential grapefruit-drug interaction situations. Patients
need accurate, specific information about the grapefruit juice-drug interaction. When educating a
patient regarding a potential grapefruit-drug interaction ask about grapefruit or grapefruit juice
consumption. In situations where a patient is taking a medication that interacts with grapefruit
juice and does not wish to stop consuming it, the pharmacist might suggest other medication
options.

Pharmacists can often predict if a new drug might be a candidate for a significant interaction
with grapefruit or its juice by looking at these characteristics:
Is it metabolized by intestinal CYP3A4?
Is it given orally?
Does it have a low bioavailability?
Does it have a narrow therapeutic index?

The following key messages should be communicated to patients:

Most medications do not interact with grapefruit juice, but if you consume grapefruit or grapefruit
juice let your physician or pharmacist know, especially when beginning a new prescription.
Alternative medications that do not interact with grapefruit may be available if you do not want to
stop drinking grapefruit juice or eating grapefruit.
 
 
5. Literature reviews
Bailey DG, et al. 1998 Aug.
Grape fruit juice-drug interactions.
 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 presystemicfelodipine 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 C(max).
Dresser GK, et al. 2004.
Interactions between grapefruit juice and cardiovascular drugs.
 Numerous medications used in the prevention or treatment of coronary artery disease and its complications have
been observed or are predicted to interact with grapefruit juice. Such interactions might also cause excessive
vasodilatation when hypertension is managed with the dihydropyridinesfelodipine, nicardipine, nifedipine,
nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In angina pectoris, administration of grapefruit
juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with
clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine,
disopyramide, or propafenone, and for the congestive heart failure drug, carvediol.
Uno T, et al.2006 May.
Effect of grapefruit juice in relation to human pharmacokinetic study.
 Grapefruit juice (GFJ) interacts with a number of drugs, and can alter pharmacokinetics parameters of the drugs. The
predominant mechanisms of GFJ-drug interaction are thought to be due primarily to the inhibition of intestinal
CYP3A4 activity without an apparent inhibition of hepatic CYP3A4. GFJ is also an inhibitor of P-glycoprotein, an
efflux pump in intestinal cell wall enterocytes, although clinical support for this mechanism remains unclear. In
addition, GFJ has recently been shown to be a potent in vitro inhibitor of the organic anion-transporting polypeptides
(OATP) 1A2, intestinal uptake transporters of structurally anionic drugs
6.Clinical significance of grapefruit drug interaction1
 After a standard oral dose of a “susceptible” drug, subjects with very low CYP3A4
activity in the intestine will tend to have a relatively high AUC. Grapefruit juice
should have a relatively small effect on pharmacokinetics in these individuals
because there is little intestinal CYP3A4 activity to inhibit. In contrast, subjects with
high intestinal CYP3A4 activity will have a marked increase in AUC when affected
drugs are taken with grapefruit juice.
 A situation in which toxicity could occur would be in patients who have been given
higher than usual doses of a susceptible drug and then begin drinking grapefruit juice
for the first time. This could occur if the physician increases the drug dose to a
desired pharmacologic effect.
 An additional situation might be when a patient has severe liver disease such that
the intestine is the major site for metabolism of the drug. Such a patient would be
expected to have high systemic exposure to the drug at usual doses; loss of intestinal
CYP3A4 activity would further increase the exposure.
 In the future it should be possible to use grapefruit-derived furanocoumarins as
additives to certain drugs to improve the oral delivery of some drugs by reducing
variability. Such formulations would obviously be no longer susceptible to grapefruit
juice interactions. It should also be possible to remove furanocoumarins from
grapefruit juice to reduce drug interaction potential.
 Finally to thoroughly assess the clinical significance of grapefruit-drug
interactions, the type and amount of grapefruit juice must also be considered. This
variation between individuals may be significant and is difficult to predict. The
grapefruit-drug interaction appears to affect patients with high quantities of small
bowel CYP3A4 isoenzymes.
7.Active components of grapefruit juice. 2, 3, 4
 Originally, naringin was thought to be the main component responsible for
grapefruit-drug interactions. However, studies have shown naringin to be a weak
inhibitor of CYP3A4. 2, 3, 4
 Furanocoumarins found in grapefruit juice as CYP3A4 inhibitors. The
furanocoumarins such as bergamottin was mainly thought to be responsible for the
inhibition of intestinal CYP enzymes. 6, 7Bergamottin is present in grapefruit juice in
concentrations ranging from 2 to 30 μmol/L. .The most abundant and probably the
most important single furanocoumarin is 6,7- dihydroxybergamottin (DHB). 1,9,10
 When bergamottin administered as a pure substance enhanced the oral
bioavailability of some drugs. However, the effect was substantially less than that
produced by grapefruit juice even at markedly higher doses of bergamottin than
normally present in the juice. It appears probable that the interaction also involves
other furanocoumarins present in whole grapefruit juice, possibly acting in
combination by additive or synergistic mechanisms. Bergamottin has systemic
availability and is metabolized to 6’, 7’- dihydroxybergamottin in humans. 10recent
reports by different groups indicate that 6’,7’-dihydroxybergamottin is a more potent
mechanism-based inactivator or inhibitor of CYP3A4.
 Orange juice has no CYP3A4-inhibiting effects. When orange juice was spiked
with a synthetic DHB, however, no significant difference between the degrees of
inhibition produced by either of the 2 citrus fruits was observed. Therefore, the DHB
component in grapefruit appears to be another potent inhibitor of CYP3A4 and is
most likely primarily responsible for the interaction.
 The furanocoumarins are divided into 6 components: 6',7'-dihydroxybergamottin (DHB), GF-I-1, bergamottin (GF-I-2), GF-I-4, GF-I-5
(bergamottin-6',7'-epoxide), and GFI- 6.12 Significant inhibition of CYP3A4 isoenzyme activity is exhibited by DHB, GF-I-1, and GF-I-4 with minimal activity exhibited by bergamottin. 11

The CYP3A4 isoenzyme, which is found in the intestine and liver, accounts for about 40% to 60% of all CYP450 isoenzymes (although it is important to note that grapefruit inhibits CYP450 in the gastrointestinal tract,
not the liver) and is involved in the majority of significant CYP450-mediated drug interactions. Inhibition of the CYP3A4 isoenzyme, either reversible or irreversible, will result in a reduced metabolism.

8.Drug metabolism by CYPs12

CYPs are the major enzymes involved in drug metabolism accounting for
75% of the total metabolism.
9.Mechanism of action of grapefruit juice components1, 9, 17, 18
 DHB and other furanocoumarins appear to reduce CYP3A4 activity by three related but
distinct mechanisms, as follows:
 (1) Competitive or reversible inhibition,
 (2) Mechanism-based inactivation (also called irreversible inhibition), and
 The first and most common mechanism is known as competitive inhibition and results from
the competition between the inhibitor and substrate for the same CYP isoenzyme required for
substrate metabolism and elimination. The effects of competitive inhibition can be observed
after administration of the first dose of the inhibitor.
 The second mechanism is known as mechanism-based inhibition and occurs with grapefruit
juice. The most potent grapefruit components causing a mechanism-based inactivation of
CYP3A4 are furanocoumarins, which bind irreversibly to CYP3A4 and permanently inactivate
the isoenzyme. The duration of mechanism based inhibition may be longer than competitive
inhibition because new CYP3A4 isoenzymes must be synthesized for activity to be restored.
Complete recovery of the CYP3A4 may take 48 to 72 hours after the last exposure to grapefruit
juice, which explains why the effects can last for at least 72 hours after drinking grapefruit juice.
Most important, because of mechanism-based inhibition, separating the administration of
grapefruit juice and substrate drug by a few hours does not minimize grapefruit drug
interactions. Pharmacists should advise patients to entirely avoid grapefruit if they are taking
medications known to significantly interact with grapefruit juice.
 In addition to the effect on CYP3A4, grapefruit juice may also inhibit the drug transporters P-
glycoprotein (P-gp) and organic anion transporting peptide (OATP). 3 P-gp is an efflux
membrane transporter pump belonging to the adenosine triphosphate-binding cassette family of
proteins. As with CYP3A4, P-gp is found in high concentrations within intestinal enterocytes,
the primary site of oral drug absorption. The role of P-gp is to actively secrete absorbed drugs
back into the intestinal lumen. After uptake by the enterocyte, the drugs are either metabolized
by CYP3A4 or pumped back out (effluxed) into the lumen by the P-gp transporter. Therefore,
inhibition of CYP3A4 or P-gp will increase blood levels of the drug substrate. 19
10.Onset, duration and magnitude of effect of grapefruit
juice on inhibition of CYP3A4 enzymes 20,21,22
 Furanocoumarins are found predominantly in the grapefruit flesh followed by the
sac, peel, and seed. The onset of the interaction can occur within 30 minutes
following intake of a single glass of grapefruit juice, and the inhibition can last up to
3 days following the last administration of grapefruit juice. The magnitude of
inhibition of CYP isoenzymes by grapefruit components appears to be greatest for
CYP3A4 and less significant for other CYP isoforms (eg, 1A2, 2C9, and 2C19).
Additionally, the interaction appears to affect CYP3A4 in the gut wall to a much
greater extent than in the liver.20
 A usual single exposure to grapefruit juice appears to impair the enteric, but not the
hepatic component of presystemic extraction of oral midazolam. The time course of
recovery from CYP3A4 inhibition after a single exposure to grapefruit juice is not
clearly established. Recovery is largely complete within three days, consistent with
enzyme regeneration after mechanism-based inhibition. 6’7’-dihydroxybergamottin
was verified as a potent mechanism-based inhibitor of some drugs by CYP3A in
vitro. 21
 Concomitant intake of high amounts of grapefruit juice and the CYP3A4 substrate
simvastatin increased the Cmax and AUC(0-∞) of simvastatin and simvastatin acid
about 5- to 15-fold. When simvastatin is taken 24 hours after ingestion of grapefruit
juice, the extent of the interaction is about 90% smaller than during concomitant
administration of simvastatin and grapefruit juice. The interaction potential of even
high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7
days after the last dose of grapefruit juice.22
 Other similar fruits and herbal products which can cause
the drug interactions9,10

Seville
 orange: Seville orange juice is not usually consumed as a juice because
of its sour taste, but it is found in marmalade and other jams. 7 When a study
was conducted to determine whether Seville orange juice produces a grapefruit
juice–like interaction with felodipine and whether bergamottin, DHB, or other
furocoumarins are involved. The results suggested that, Seville orange juice and
grapefruit juice interact with felodipine by a common mechanism, which is
probably inactivation of intestinal CYP3A4.Bergamottin and DHB may be
“marker substances” in foods for this interaction. The lack of interaction
between Seville orange juice and cyclosporine suggests that grapefruit juice
may also inhibit intestinal P-gp, whereas Seville orange juice may selectively
“knock out” intestinal CYP3A4.9, 10 Wheather lemon juice interacts with drug is
unknown.
Red wine: Like grapefruit juice, red wine also contains a complex mixture of

molecules including flavonoids and other polyphenols. These electron rich
molecules are likely substrates for CYP3A4 and may also inhibit the enzyme.
 
Table 1 Possible interactions between grapefruit juice (GJ)* and drugs
metabolized by CYP3A4.14
Drug Class Drug Possible Adverse Increased Oral Management
Effects Bioavailability
Antiarrhythmics Amiodarone Arrhythmias Yes Avoid GJ
Quinidine None No None
Antibiotics Clarithromycin None No None
Antihistamines Terfenadine Arrhythmias, Yes Avoid GJ
prolonged Q-T
interval
Anxiolytics Diazepam Increased Seditation Yes Avoid GJ
Midazolam “ Yes Avoid GJ
Triazolam “ Yes Avoid GJ
Calcium channel Amlodipine Tachycardia, Yes Avoid GJ
blockers Hypotension
Felodipine “ Yes Avoid GJ
Nifedipine “ Yes Avoid GJ
Diltiazem None No None

HMG COA Atorvastatin Myopathy, Yes Avoid GJ

reductase inhibitors Headache,
Lovastatin “ Yes Avoid GJ
Pravastatin “ Yes Avoid GJ
Simvastatin “ Yes Avoid GJ

Immunosupressants Cyclosporine Renal/hepatic Yes Avoid GJ

dysfunction,
increased
Other Carvedilol Bradycardia, Possible Monitor for side
effects
11.Grapefruit juice and drug interactions
Benzodiazepines31,32

 Many benzodiazepines, including midazolam and triazolam, are substrates of CYP3A4 and are
metabolized by hepatic and intestinal CYP3A4. Coadministration with grapefruit juice did not alter the
pharmacokinetics and pharmacodynamics of intravenous midazolam. After an oral dose of midazolam,
however, grapefruit juice significantly increased the peak plasma concentration by 56% and the area under
the curve (AUC) by 52%.26These changes were associated with significant alterations in the
pharmacodynamic effects of midazolam, such as delay of the reaction time. Additionally, grapefruit juice
increased the AUC (by 50%) and the peak plasma concentration (by 30%) of triazolam in healthy
volunteers and was associated with increased drowsiness. Caution must be taken when giving oral
midazolam, particularly in patients with other causes for increases in midazolam bioavailability, such as
advanced age, liver cirrhosis, and coadministration of other CYP3A4 inhibitors. All of these conditions
may potentiate the effects of grapefruit juice.
Immunosuppressants33
 Cyclosporine is an immunosuppressant used widely in solid organ and bone marrow transplantation as
well as in the treatment of psoriasis. Oral cyclosporine formulations (ie, oil/water and microemulsion)
have been well documented to interact with grapefruit juice through inhibition of CYP3A4 and P-gp.
However, intravenous cyclosporine formulations do not interact. In one study, the mean absolute oral
bioavailability of cyclosporine increased by 62% with grapefruit juice administration, but there was no
significant effect with intravenous cyclosporine.33 The magnitude of pharmacokinetic changes associated
with the grapefruitcyclosporine interaction is variable and unpredictable within individuals and should not
be used as a strategy to reduce cyclosporine dosages and save on drug costs.
Calcium channel blockers34,35
 The dihydropyridine calcium channel blockers, felodipine, nifedipine, nisoldipine, and nitrendipine, are
substrates of CYP3A4 and undergo extensive first-pass metabolism by hepatic and intestinal CYP3A4.
When grapefruit juice is administered in combination with oral felodipine, concentrations of felodipine
increase significantly compared with felodipine alone. When felodipine was administered intravenously
with oral grapefruit juice, the plasma concentration of felodipine was not significantly altered.
HMG-CoA Reductase Inhibitors (Statins)36
 A study showed that 2 days of pretreatment with 200 mL doublestrength
grapefruit juice 3 times a day, as compared with water, prior to administration of
lovastatin 80 mg increased the peak concentrations of lovastatin and the
metabolite, lovastatin acid, by 12- and 4-fold, respectively. The results of these
studies suggest that concomitant administration of grapefruit juice with lovastatin
should be avoided. Potentially serious adverse reactions due to elevated levels of
statins and metabolites .

 The following drugs definitely interact with CYP3A4:24,25,26

 Valproate semisodium, carbamazepine, digoxin, buspirone Benzodiazepines
including: alprazolam, diazepam, midazolam, loxazepam.

 Additional drugs found to be affected by grapefruit juice include27,28,29

 Statins such as atorvastatin, lovastatin,and simvastatin. Dihydropyridines
including felodipine nitrendipine, lAntiarrhythmics including amiodarone,
quinidine ,carvediol.
12.Management of Grapefruit-Drug Interactions 41,42,43
 Grapefruit is a healthy addition to a well-balanced diet.
However, the fruit has been shown to affect the metabolism of
many medications, increasing the risk of toxicity and adverse
effects. Characteristics of oral medications that may interact
with grapefruit include extensive metabolism through the
intestinal cytochrome P450 3A4 system, low bioavailability, and
a narrow therapeutic index. Prominent medications known to
interact with grapefruit include statins, antiarrhythmic agents,
immunosuppressive agents, and calcium channel blockers.
 There are equally effective alternatives to these drug classes
that do not have the potential to interact with grapefruit. These
alternative drugs may be substituted if a patient experiences or
is at risk of a grapefruit-drug interaction. Patients also may
choose to exclude grapefruit from their diets and consume other
fruits, including other types of citrus, to avoid an interaction.
Grapefruit-Drug Interactions and Alternative Therapies
45,46,47
Drug Class Drugs Potentially affected Effect of Interaction Alternative Treatments
by grapefruit
Antiarrhythmics Amiodarone Increased plasma Digoxin , diltiazem
concentrations of amiodarone Verapamil
may cause thyroid or
pulmonary toxicity, liver
injury, QTc prolongation
,bradycardia,

Calcium channel blockers Felodipine Increased plasma Amlodipine diltiazem ,

nifedipine concentration may lead to verapamil
flushing, peripheral edema,
headaches, tachycardia
hypotension,and myocardial
infraction

Statins Atorvastatin, lovastatin Increased plasma

simvastatin concentration may cause Fibric acids nicotinic acid, or
headaches, Pravastatin bile acid sequestrants
gastrointestinal complaints,
hepatic inflammation,
myopathies

Immunosuppressants Cyclosporine Increased drug exposure may No alternatives Available

cause increased adverse
events or toxicity evidenced
by renal toxicity, hepatic
toxicity, and increased
immunosuppression.
13.Conclusion
 A glass of grapefruit juice has the potential to augment the oral bioavailability and to
enhance the beneficial or adverse effect of a broad range of medication, even the juice
consumed hours before. The grapefruit juice acts by inhibiting presystemic drug
metabolism mediated by CYP3A4 isoform in small bowel.
 Considering how to manage grapefruit drug interactions, a pharmacist should be
competent enough to decide whether the interaction is clinically relevant. A number of
medications are reported to have interactions with grapefruit. However many of the
other medications have not been proven clinically significant to have interaction. The
importance of clearly understanding possible interactions with grapefruit products is
becoming more evident. The physicians, pharmacists and other health professionals
should educate patients about consumption of grapefruit juice with medication.
 There are several other fruit juices available as substitute for grapefruit juice,
including orange juice as a first choice.
 The recent studies on recovery of the intestinal CYP3A4 enzymes after consuming
grapefruit juice suggest that during the clinical trials and pharmacokinetic studies,
grapefruit juice should be avoided at least for 72 hours rather than 48 hours or less so
that possible inter-subject variability in pharmacokinetic parameters can be reduced.
 It is recommended that drugs possibly interacting with grapefruit juice should be
appropriately labeled.
 The serendipitous observation of increased plasma felodipine concentration by
grapefruit juice, provided fundamental new knowledge to stimulate further researches
required to understand the interactions of GJ with medications and to determine amount
of GJ considered safe for administration with drugs and with different patient
populations.
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