CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 5, September/October 2010
282
AFRICA
pronounced decrease in diastolic blood pressure, increase in
haemodynamic-related adverse effects, such as increased heart
rate and orthostatic hypotension have been reported when
felodipine was taken concurrently with grapefruit juice.
47,48
Similarly, concurrent administration of grapefruit juice with
HMG-CoA reductase inhibitors, such as atorvastatin, lovastatin
or simvastatin at high doses may increase the risk of rhabdomy-
olysis.
44,49,50
With the current trend towards more aggressive lipid-
lowering therapy with the statins, the risk of rhabdomylosis is
even greater in patients taking grapefruit juice concomitantly.
51
A
possible case of potentiation of the antiplatelet effect of cilosta-
zol by grapefruit juice, leading to purpura has been reported by
Taniguchi
et al.
52
Liver cirrhosis patients are more dependent on intestinal
CYP3A4 for drug metabolism,
1
and are, therefore, at increased
risk. The elderly are particularly vulnerable to grapefruit-induced
drug interactions, since they are often on multiple medications,
and they experience diminished drug disposition capacity.
48,53,54
Genetic polymorphism of the CYP3A4 enzyme would be
expected to influence the potential for grapefruit–drug inter-
action to occur in a patient. Patients who express high levels
of intestinal CYP3A4 would extensively metabolise substrate
drugs, and hence experience a greater impact of grapefruit juice–
drug interactions and
vice versa
. However, no large-scale geno-
typing data is available for conclusive evidence in this regard.
Positive aspects of grapefruit-induced drug interactions would
be related to a potential reduction in costs incurred on reduced
treatment regimens of different ailments. Grapefruit contains a
number of health-promoting compounds, which may be exploit-
ed for therapeutic use. Traditionally, grapefruit–drug interac-
tions have been viewed in terms of enhancement of unwanted
adverse effects. But recently, attempts have been made to limit
such effects by either modifying the chemistry of the chemical
constituents of grapefruit juice, or eliminating them altogether.
Various laboratories have synthesised furanocoumarin dimers,
which are believed to be as potent as the natural forms but selec-
tive in their inhibition of CYP3A4.
55,56
It is believed that such
dimers may be therapeutically exploited to customise grapefruit–
drug interactions to specific patients’ needs. A furanocoumarin-
free grapefruit juice created by using food-grade solvents and
absorption resins failed to inhibit CP3A4 activity and did not
increase felodipne’s bioavailability in healthy human volunteers,
thus confirming that furanocoumarins are the actual ingredients
in grapefruit that enhance felodipine’s bioavailability.
57
A recent study by Myung
et al
.
58
has suggested that auto-
claved edible fungi (
Morchella esculenta
,
Monascus pupureus
,
Pleuratus sapidus
and
Agarisu bisporus
) bind bergamottin
and 6
′
,7
′
-dihydroxybergamottin, and can therefore be used to
remove furancoumarins from grapefruit juice without affecting
its nutritional quality. Previous studies have suggested that heat
treatment or UV radiation inactivates bergamottin and 6
′
,7
′
-dihy-
droxybergamottin in grapefruit juice, and therefore eliminates
the pharmacokinetic interaction of grapefruit juice with drugs.
59,60
Clinical benefits of such interventions are yet to be seen.
Grapefruit–drug interactions have not, surprisingly, been
studied in other organs such as the liver. It is not understood why
grapefruit would inhibit intestinal but not hepatic CYP3A4. Is
it because the quantities of grapefruit juice used in such clinical
studies were not large enough to influence hepatic metabolism?
However, our laboratory recently reported a drug interaction of
a different kind. We observed that grapefruit juice exacerbates
metformin-induced lactic acidosis in rats
in vivo
by facilitating
metformin uptake by hepatocytes.
61
Clearly, the clinical implica-
tions of such a finding are significant, given that another bigua-
nide, phenformin was withdrawn from the market when 50% of
the patients who took it died due to lactic acidosis.
62
Grapefruit and the metabolic syndrome
The metabolic syndrome is a cluster of metabolic abnormalities
(currently defined by abdominal obesity, atherogenic dyslipi-
daemia, raised blood pressure, insulin resistance and or glucose
intolerance, pro-inflammatory state and thrombotic state
63
),
which increase the risk of developing diabetes and other cardio-
vascular diseases. Exercise and dietary intake are two of the
interventions currently being advocated for among the general
public.
Grapefruit has been part of many diets since its incorporation
into the ‘Hollywood’ diet of hard-boiled eggs, green vegetables
and ‘melba’ toast in 1930 as an anti-obesity ingredient.
64
A
recent study by Fujioka
et al
.
65
has reported that consumption of
whole grapefruit or grapefruit juice is associated with significant
weight loss and improved insulin resistance in patients with the
metabolic syndrome, compared to placebo. Consumption of
grapefruit may, therefore, have beneficial effects in patients with
type 2 diabetes mellitus and other degenerative diseases, which
may scientifically justify the age-old tradition of dietary supple-
mentation with grapefruit.
Grapefruit consumption has been associated with decreased
fasting blood glucose and insulin levels, and serum total choles-
terol, low-density lipoprotein and triglyceride levels.
61,66
So much
attention has been paid to grapefruit–drug interactions that, to
date, the role of grapefruit in prevention of the development of
the metabolic syndrome, despite decades of advocacy, is not fully
understood.
Dietary flavonoids have been identified as anti-diabetic and
may reduce the risk of age-related chronic diseases.
67
The major
flavanones in grapefruit are naringin and hesperidin,
1,12
and many
laboratories have attempted to probe whether these flavonoids
may be linked to the reduced risk of degenerative diseases
associated with grapefruit consumption. Naringin, like insulin,
has been shown to decrease microsomal triglyceride transfer
protein [necessary for hepatocyte assembly and secretion of
apolipoprotein (apo)B-containing lipoproteins which confer an
increased atherosclerotic risk] expression
in vitro
.
68
This there-
fore suggests that naringin may be useful in activating insulin-
signalling pathways important for the regulation of hepatocyte
lipid metabolism.
Combined treatment with naringin and vitamin C has been
demonstrated to ameliorate streptozotocin-induced diabetes in
rats.
69
Jung
et al
.
70,71
have reported that hesperidin and naringin
are beneficial for improving hyperlipidaemia and hyperglycae-
mia in type 2 diabetic animal models by partly regulating fatty
acid and cholesterol metabolism and affecting gene expression
of glucose-regulating enzymes. Preliminary results from our
laboratory also indicate that grapefruit juice regulates the activi-
ties of hepatic glucose-6-phosphatase and phosphoenolpyruvate
carboxykinase, respectively, in rats.
72
All these results vindicate flavonoids in the anti-diabetic
effects of grapefruit. However, it is still not clear whether
