CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 5, September/October 2010
AFRICA
281
dipine, amlodipine and nifedipine.
16-21
That the degree of interaction appears to correlate with the
oral bioavailability of these drugs, and that the interaction does
not affect intravenously administered drugs led researchers
to suspect as the main culprit the intestinal cytochrome P450
(CYP3A4), which metabolises these drugs and many others. It
has now been established that the bioactive chemical compounds
(furanocoumarins: bergamottin and 6
′
, 7
′
-dihydroxybergamottin)
present in grapefruit inhibit intestinal CYP3A4 activity through
a mechanism-based reaction, which causes degradation of the
enzyme, hence reducing its levels by as much as 47% within
four hours after grapefruit juice ingestion.
1,14,22-24
It therefore
follows that calcium channel blockers, which are extensively
metabolised by intestinal CYP3A4, have low oral bioavailability,
and are, therefore, most affected by grapefruit inhibition of this
enzyme.
Drug interactions with grapefruit juice are not confined to
inhibition of only CYP3A4, but also other drug-metabolising
cytochrome P450 enzymes such as CYP2C6, CYP2D6, CYP2J2,
CYP2C19 and CYP2E1 and many others.
25-29
Drug transporter
proteins such as p-glycoprotein (P-gp) and organic anion trans-
porter proteins (OATP) that facilitate drug efflux/influx in the
enterocytes have been shown to interact with grapefruit,
30,31
but
the specific mechanism of this interaction is still contentious.
Both the P-gp and CYP3A4 appear to act synergistically as a
barrier to many orally administered drugs.
Cardiovascular drug substrates of P-gp include carvedilol,
talinolol, diltiazem, verapamil, simvastatin and lovastatin.
13,32-35
However, an interesting observation has been made that despite
the fact that digoxin is a strong substrate of P-g, its bioavailabil-
ity is not affected by grapefruit.
36
It has since been argued that it
is the high oral bioavailability of digoxin (70–80%), rather than
lack of grapefruit effect on P-gp, that contributes to its reduced
absorption.
37,38
Unlike calcium channel blockers, angiotensin converting
enzyme (ACE) inhibitors have not shown any significant inter-
action with grapefruit juice. However, grapefruit juice has been
shown to inhibit the bioactivation of the angiotensin receptor
blocker losartan to its active metabolite, thus reducing its effi-
cacy.
39
Thiazide diuretics and
α
1
-adrenergic antagonists, such as
doxasozin, terasozin and prazosin, have so far shown no interac-
tion with grapefruit juice.
40
However, grapefruit juice completely
inhibited the conversion of the anti-arrythmic prodrug amio-
darone to its active metabolite, N-desthylamiodarone, resulting
in 50 and 84% increases in area-under-the-curve (AUC) and
maximum plasma concentrations, respectively, of amiodarone.
This led to clinical prolongation of QT intervals and torsades de
pointes, particularly in patients with pre-existing heart disease or
other risk factors, such as hypokalaemia.
14,41
Among the cholesterol-lowering agents, grapefruit is known
to increase serum concentrations of simvastatin and its active
metabolite, simvastatin acid, and this interaction subsides within
three to seven days after ingestion of the last dose of grapefruit
juice.
42,43
Similar observations have been made (to a lesser extent
though) when other HMG-CoA reductase inhibitors, such as
lovastatin and atorvastatin are taken concurrently with grapefruit
juice.
14
However, pravastatin’s (not metabolised in the body)
bioavailability was not affected by ingestion of grapefruit juice,
indicating that grapefruit juice’s effect on HMG-CoA reductase
inhibitors is a consequence of intestinal metabolism of such
drugs.
44
Other cholesterol-lowering agents such as nicotinic acid
and common fibric acid derivatives as well as bile acid seques-
trants have not been reported to interact with grapefruit juice.
40
Although grapefruit–drug interactions have been documented
in over 225 publications in the scientific literature, involving
more than 25 drugs,
45
the clinical impact on inhibition of intesti-
nal drug metabolism by CYP3A4 has not been fully investigated,
and the information available in biomedical literature is largely
built on speculations from
in vitro
experiments and a few clini-
cal studies. Evidence gathered so far, therefore, indicates that
grapefruit–drug interactions occur when the drug in question
is a substrate of CYP3A4, the drug has an inherently low oral
bioavailability due to enteric CYP 3A4 metabolism, and when
the individual patient expresses sufficient quantities of CYP3A4.
Despite the large volume of literature available on this subject,
only a few clinical case reports have been documented on grape-
fruit juice–drug interactions, perhaps because many such cases
go unreported.
It is envisaged that grapefruit juice interaction with calcium
channel blockers may result in excessive vasodilatation, with
symptoms of tachycardia, flushing or hypotension.
46
However,
Fig. 1. Enzymatic hydrolysis of naringin. Naringinase is an enzymatic complex with
α
-rhamnosidase activity which
hydrolyses naringin to prunin and rhamnose, and
β
-glucosidase activity, which in turn hydrolyses prunin to narin-
genin and glucose, respectively. Rha-Glc
=
rhamnoglucose.
12
Naringin
Rha–Glc-0
0H
0H
0
0
Naringinase
Enzyme
Complex
Naringenin
Glucose
H0
0H
0H
0
0
CH
2
0H
H C
0 0H
H
H
H
C
C
C
H0
H
0H
C 0H
