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Interactions of herbs and food products with drugs
Grapefruit juice as an example
Inder Pal Singh*, Sandip B Bharate and K K Bhutani
Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER)
Sector-67, SAS Nagar-160 062, Punjab, India
*Correspondent author, E-mail: [email protected]
Abstract
Plants have been used throughout human history for their medicinal
properties and herbal medicines are popular worldwide. Since, all herbal
medicines are mixtures of more than one active ingredient, such combinations
of many substances obviously increase the likelihood of interactions taking place.
Although herbal medicines have been used as remedies for number of illnesses,
many of them have shown interactions with the synthetic drugs and also exhibited
adverse effects. These herb-drug interactions may be adverse as well as beneficial.
Herb-drug interactions are discussed in this article with an example of Grapefruit
(Citrus paradisi Macf.) juice-drug interaction. The oral bioavailability of many
drugs was found to be increased when these are consumed along with grapefruit
juice.
Keywords: Herb-drug interactions, Grapefruit juice, Citrus paradisi,
Furanocoumarin.
IPC code; Int. cl.7— A61K 35/78, A23L 2/06
Introduction
There is a global resurgence in
the use of herbal medicines. An estimated
one third of adults in the Western world
use alternative therapies, including
herbs1,2. These herbs may be used either
in their primary forms or combined into
mixtures. In contrast to chemical drugs,
herbs are generally claimed to be nontoxic, because of their natural origin and
long-term use as folk medicines. However,
problems arising due to intrinsic toxicity,
adulteration, substitution, contamination,
misidentification, drug-herb interactions,
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and lack of standardization are generally
overlooked3,4. Herbs may increase or
decrease the effects of some medications
when taken together. There are increasing
reports on adverse drug reactions and
poisonings associated with the use of
herbal medicines as well as dietary
supplements and food products5-7.
Citrus paradisi
often difficult to analyze these interactions
as these herbal remedies contain many
substances and mostly are of variable and
undefined composition. Herbal drugs
show interaction with drugs and such
interactions may often be serious or even
life threatening, for example, Ginkgo
biloba Linn. raised blood pressure when
combined with Thiazide and cause coma
when combined with Trazodone6. On the
other hand these interactions may also be
beneficial in some cases7. Importantly,
majority of people who use herbal
medicines concurrently with prescribed
or over the counter medicines do not
Herb-drug Interactions
All herbal medicines are mixtures
of more than one active ingredient; there
is a likelihood of interactions between
combinations of these substances. It is
Sliced Grapefruit
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reveal this use to their physician or
pharmacist, thereby greatly increasing the
risk of side effects from the interactions
between herbal components and
concurrent pharmacotherapy8. Moreover,
because most herbal product purchases
occur outside the pharmacy, concurrent
use of herbal products and prescription
drugs often evades the attention of the
pharmacist and physician. As such, the use
of herbal products often escapes standard
mechanisms for protecting persons from
harmful effects of drugs and drug
interactions8,9.
St. John’s wort (Hypericum
perforatum Linn.) is extremely popular
in US and Europe and is used to treat
wounds, gastritis, kidney and lung
disorders, insomnia and depression.
However, recent data have revealed
dangerous interactions of St. John’s wort
with several drugs such as Indinavir and
Cyclosporin. Blood levels of Indinavir, a
drug prescribed to treat HIV infection,
decrease to such low levels (81%) when
taken together with the herb that the drug
no longer remains effective10,11. Similarly,
Cyclosporin given to heart transplant
patients to prevent their immune system
from rejecting transplant organs, when
taken together with the herb falls to
subtherapeutic level prompting episodes
of rejection. However, Cyclosporin
concentration returned to therapeutic
levels with discontinuation of St. John’s
wort12,13. St John’s wort also lowers blood
concentration of Amitryptyline, Digoxin,
Warfarin and Theophylline. It causes
intermenstrual bleeding when used with
oral contraceptives (ethinyl estradiol) and
delirium when used together with selective
serotonin re-uptake inhibitors5. St. John’s
Table 1 : Herb-drug interactions23-26
Herb
Drug
Interaction
Aloe vera
Bitter melon
Capsicum
Digoxin and Thiazide
Hypoglycaemics
Aspirin
ACE inhibitors
Theophylin
Corticosteroids
Warfarin
Anticonvulsants
Caffeine
Hypoglycaemics
Antihypertensive drugs
Hypoglycaemics
Aspirin/Warfarin
Acetaminofen
Anticonvulsants/TCA
Thiazides
Calcium channel blockers and many drugs
Antihypertensives, Digoxin
Loop diuretics
Antihypertensives
Barbiturates
Cyclosporin/Digoxin
Indinavir, Midazolam
5-HT reuptake inhibitors
Increase cardiac toxicity
May affect blood glucose levels
Protects against stomach irritation
May increase cough
May increase absorption
Avoid combination
Decrease Warfarin metabolism
Herb may cause seizures
Herb may increase nervousness
May cause hyperglycaemia
Herb may decrease BP
Herb may cause hypoglycaemia
Irreversible inhibition of Platelet aggregation
Subarachnoid haemorrhage
Increase seizures
May lead to hypertension
Increases oral bioavailablity
Herb may cause hypokalemia
Sodium and fluid retention
May increase BP
May decrease barbiturate-induced sleeping time
Herb may decrease levels of these
drugs via metabolism
Additive effect
Echinacea
Ephedra
Garlic
Ginkgo biloba
Grapefruit
Licorice
St. John’s wort
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wort is known to increase cytochrome 3. Protection from adverse effects
human case report (per os) the
P 450 isozymes that are responsible for
— Several herbs such as cayenne
antiparkinsonian
effect
of
metabolism and elimination of many
pepper, licorice, milk thistle
phenothiazines such as Flupenthixol
drugs. Ginseng (Panax ginseng Mey.)
(Silybum marianum Gaertn.)
and Fluphenazine and anticholinergic
lowers blood concentration of alcohol
and Zingiber officinale Rosc. may
effect of Procyclidine are reduced
and Warfarin and induces mania if used
provide protection against the adverse
when administered with Arecoline
together with Phenelzine 5. Similarly,
effects of drugs. Prior administration
and that could be due to the
Ayurvedic formulation Shankhapushpi
of ginger acetone extract can prevent
Cholinergic effect of the later14.
leads to decreased blood concentrations
cyclophosphamide
induced
Grapefruit juice–Drug
of Phenytoin6. Some other herb-drug
vomiting14.
interactions are enlisted in the Table 1 to 4. Enhancement of drug effect — interactions
highlight the risks associated with
Foods are intended to be safe for
The effects of drugs may be enhanced
concurrent use of herbal remedies and
by a mechanism dissimilar from that human consumption, but at the same
prescription drugs.
of the drug, for example, by time, few foods can produce an
There are following possible ways
bromelian [Ananas comosus interaction with drugs by altering their
in which herb-drug interaction may occur.
(Linn.) Merrill]. Hypokalemia pharmacokinetics and subsequent clinical
resulting from a long-term use of response. For example, grapefruit juice
1. Decrease in the bioavailability of
stimulant laxative herb potentiates the has been shown to increase the oral
the drug — This may occur by (i)
effect of cardiotonic and anti- bioavailability of more than 20 drugs from
reduction of the absorption of the
a diverse range of therapeutic categories
arrhythmic drugs like Quinidine15.
drug {Amorphophallus konjac
K. Koch, tea [Camellia sinensis 5. Additive effect — Similar activities (Table 2).
Grapefruit, botanically named as
of the herb and the drug lead to an
(Linn.) O. Kuntze], guar gum
additive effect. Some examples are Citrus paradisi Macf. (Hindi ⎯
[Cyamopsis tetragonolobus
Aloe, betelnut (Areca catechu Chakotra) of Rutaceae family, is
(Linn.) Taub.] and Plantago spp.};
Linn.), gingko, licorice, gurmar indigenous to West-Indies (Jamaica) and
(ii) enhancement of metabolism
(Gymnema sylvestre R. Br., cultivated in India both in subtropical and
(mustard); or (iii) enhancement of
leaves), bitter melon (Momordica tropical areas, mostly in Punjab, the
elimination (coffee)14.
western parts of Uttar Pradesh and to
charantia Linn., fruit and juices),
2. Increase in the bioavailability of
places around Pune in Maharashtra.
and kava (Piper methysticum G.
the drug — The bioavailability of
‘Duncan’ variety is being grown
Forst.). The hypoglycaemic effect of
drug can be enhanced by (i) increase
commercially in India. In view of the
oral antidiabetic drug was increased
of the absorption of the drug as with
consumption of grapefruit juice in India,
when associated with gurmar in
cayenne pepper (Capsicum spp.)
it is important that people should be
human clinical trial. The gurmar is
or black pepper (Piper nigrum
aware of potential risks associated with
used as antidiabetic remedy in
Linn.), or (ii) reduction in the
concurrent use of grapefruit juice and
Chinese traditional medicine. The low
metabolism (as with citrus and
drugs.
absorption of dietary carbohydrates
licorice). The oral drug absorption
Grapefruits are high in pectin and
can
lead
to
the
reduction
of
insulin
can be increased by Zingiber
lycopene that help lower blood cholesterol
dose in insulin-dependant patients16.
officinale Rosc. Piperine, which is
and the risk of cancer, respectively.
a known bioavailability enhancer 6. Antagonistic
effect
— However, it also inhibits cytochrome P450
increases absorption of Phenytoin and
Antagonism or incompatibility may 3A4 (CYP3A4), an enzyme that is
Propranolol and slows down the
occur with betelnut, mustard, and responsible for metabolism and
14
elimination of both drugs .
papaya (Carica papaya Linn.). In absorption of many drugs. This inhibition
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Table 2 : Drugs interacting
with grapefruit juice
Anti-infective agents
Artemether27
Saquinavir28
Antilipidemic agents
Atorvastatin29
Lovastatin30
Simvastatin31
Cardiovascular agents
Carvedilol32
Felodipine33
Nifedipine20
Nisoldipine20
Nicardipine20
Nitrendipine20
Nimodipine34
Verapamil20
Antimalarial agents
Halofantrine35
Central nervous system agents
Buspirone36
Carbamazepine37
Diazepam38
Triazolam39
Estrogens20
Ethinyl estradiol (INN,
ethinylestradiol) 20
Gastrointestinal agents
Cisapride40,41
Histamine H1-antagonists
Terfenadine20
Immunosuppressive agents
Cyclosporine (INN, cyclosporin) 20
Tacrolimus42
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causes blood levels of these medications
to increase, which can lead to toxic side
effects from these medications. Substances
in grapefruit juice appear to be
metabolized to chemically reactive
intermediates that covalently bind to
CYP3A4, resulting in irreversible enzyme
inactivation, a process termed suicide or
mechanism-based inhibition17.
It was an accidental discovery
when grapefruit juice used to mask the
taste of ethanol in a study involving the
calcium channel blocker Felodipine, was
found to increase its oral availability18.
Since then, grapefruit juice has been
shown to enhance oral availability of more
than a dozen different drugs19. These
include antihistamines (Terfenadine),
cholesterol lowering drugs (Statins),
psychiatric medications (Triazolam,
Diazepam), calcium channel blockers
(Felodipine) and immunosuppressant
drugs (Cyclosporine)20. Some drugs such
as Terfenadine require 100% breakdown
by ‘first-pass’ metabolic pathway to
convert it to its active and less toxic
metabolite. Any drug or food such as
grapefruit, which inhibits CYP3A4 will
block this metabolic pathway resulting in
absorption of unmetabolized Terfenadine,
that may result in cardiac arrest and
death20.
Most of the drugs affected by
grapefruit juice have poor and highly
variable oral bioavailability. Additionally,
most of these drugs are mainly
metabolized in the body by CYP3A4, an
enzyme present in the liver and intestine.
The major effect of grapefruit juice
appears to be to reduce ‘first-pass’
metabolism by reducing CYP3A4 activity7.
Because grapefruit juice does not
generally affect the systemic clearance of
affected drugs, it seems that grapefruit
juice may selectively reduce intestinal
CYP3A4 activity while having little effect
on liver CYP3A4. Although a variety of juice
components have been implicated, the
major active ingredients appear to be
furanocoumarins. The most abundant and
probably the most important single
furanocoumarin is 6', 7'-dihydroxybergamottin (DHB). DHB and other
furanocoumarins appear to reduce
CYP3A4 activity by three related but distinct
mechanisms: (1) competitive or
reversible inhibition, (2) mechanismbased inactivation, and (3) actual loss of
CYP3A4 enzyme. In the future it would be
possible to use grapefruit-derived
furanocoumarins as additives to certain
drugs to improve the oral delivery of some
drugs17.
Role of Bergamottin in grapefruit
juice effect
Although grapefruit juice
contains a number of diverse components,
accumulating evidence indicates that
furanocoumarins are important CYP3A4
inhibitors. Accordingly, furanocoumarins
have been proposed as the primary
components responsible for grapefruit
juice-drug interactions. The two most
abundant furanocoumarins present in the
juice are bergamottin and 6', 7'dihydroxy-bergamottin
(DHB).
Bergamottin is the parent furanocoumarin
and has been shown to be both a reversible
and a mechanism-based inhibitor of
CYP3A4. The reactive metabolites of
bergamottin are not known, but it may
undergo oxidation to form a reactive
furanoepoxide that covalently binds to
CYP3A421. DHB, as its name implies, is a
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