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REVIEW ON DRUG INTERACTIONS WITH GRAPEFRUIT JUICE
REVIEW ON DRUG INTERACTIONS WITH GRAPEFRUIT JUICE
GRAPEFRUIT JUICE
Bachelor of Pharmacy
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 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.
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
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