REVIEW

Grapefruit Juice and Statins

Jonathan W. Lee, BS, Joan K. Morris, PhD, Nicholas J. Wald, FRS
Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London,
London, UK.

ABSTRACT

We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3
widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by
about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80%
(whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density
lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by
37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same
time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If
the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for
atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to
the increased effective statin dose is minimal compared with the greater effect in preventing heart disease.
Grapefruit juice should not be contraindicated in people taking statins.
Ó 2016 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2016) 129, 26-29

KEYWORDS: Drug interaction; Effect enhancer; Grapefruit juice; Ischemic heart disease; LDL cholesterol; Statins

Current medical advice is to avoid grapefruit juice con-
sumption while taking a statin.1-3 The action of grapefruit
juice on the effect of drugs was discovered by accident in 1989
in an experiment designed to examine the effect of ethanol on
the action of felodipine, a calcium channel blocker.4 Grape-
fruit juice was used to mask the taste of alcohol but the results
showed several-fold higher felodipine concentration in blood
plasma than had been expected. Grapefruit juice has since
been shown to interact with over 85 drugs, including statins,5
which are widely used to reduce low-density lipoprotein
(LDL) cholesterol to help prevent cardiovascular disease.6
The adverse effects of statins on muscles can range from
mild discomfort (myalgia) to the more serious rhabdomyolysis,
which requires hospitalization and, in extremely rare cases,
Funding: None.
Conflict of Interest: NJW jointly holds European, Canadian, and US
patents (EU1272220 priority date April 10, 2000) for a combination pill for
the prevention of cardiovascular disease, and has an interest in its
development.
Authorship: All authors had access to the data and a role in writing the
manuscript.
Requests for reprints should be addressed to Nicholas J. Wald, FRS,
Wolfson Institute of Preventive Medicine, Barts and The London School of
Medicine and Dentistry, Queen Mary University of London, London
EC1M6BQ, UK.
E-mail address: n.j.wald@qmul.ac.uk
causes death. Statins increase the risk of hyperglycemia, but
the much greater cardiovascular benefits of statins outweigh
this small increased risk, and statins are recommended in
patients with diabetes. We here focus on rhabdomyolysis as the
dominant adverse event of concern.
This review summarizes the pharmacokinetics of grape-
fruit juiceestatin interactions, specifically, atorvastatin,
simvastatin, and lovastatin, and quantifies how this inter-
action affects LDL cholesterol and ischemic heart disease
risk and the risk of rhabdomyolysis, presenting results on
which clinical advice can be based.
CHEMISTRY OF THE GRAPEFRUIT JUICE EFFECT
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA) reductase inhibitors. Different statins vary in their
bioavailability, half-life, and method of metabolic degrada-
tion (see Table 1).6 For example, as a consequence of their
different half-lives, atorvastatin can be taken at any time
during the day with a consistent efficacy, whereas simva-
statin should be taken at night. Cytochrome P450 (CYP)
3A4 is the major enzyme involved in the metabolic degra-
dation of many statins, including atorvastatin, simvastatin,
and lovastatin.7-12
The main agents responsible for the grapefruit juice
effect on statins are bergamottin in fresh grapefruit and its

0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2015.07.036
Lee et al Grapefruit Juice and Statins 27

derivative, 60 ,70 -dihydroxybergamottin (DHB) in juice than the study that observed a 3.6-fold increase with sim-
concentrate, which are furanocoumarins.13 Furanocoumar- vastatin and grapefruit juice both taken in the morning.
ins are also found in other fruit (eg, pomegranates), and in Another study11 observed a 1.8-fold increase in the blood
vegetables (eg, parsnips and celery), however, they are levels of 10 mg of atorvastatin when taken with grapefruit
especially concentrated in grapefruit juice and fresh grape- juice. This effect would be expected to be unaffected by the
fruits.14-16 time of taking the grapefruit juice because the half-life of
Kinetic studies reveal that both atorvastatin is relatively long.
bergamottin and DHB inactivate
CYP3A4. Studies have shown a CLINICAL SIGNIFICANCE
50% reduction in intestinal
Grapefruit juice enhances the efficacy of CLINICAL IMPLICATIONS OF
CYP3A4 concentration within 4 certain statins in reducing low-density CONSUMING GRAPEFRUIT
hours of drinking one serving of JUICE WITH STATINS
lipoprotein cholesterol and heart disease.
grapefruit juice (equivalent to the
juice in one whole grapefruit).15,17
Recognizing the grapefruit juice effect Effect on LDL Cholesterol
Inhibiting the activity of CYP3A4 as an effect enhancer and therapeutic and Heart Disease Risk
in the intestines presumably in- benefit is already seen in cancer A meta-analysis by Law et al21
hibits the presystemic degradation treatment. estimated that 10 mg atorvastatin,
of statins and so increases their 40 mg simvastatin, or 40 mg
systemic bioavailability. Lova-
Moderate grapefruit juice consumption
lovastatin reduce LDL cholesterol
statin, simvastatin, and atorvastatin should not be regarded as contra- by 37%, and double these doses
are all metabolized by CYP3A4, indicated in people taking statins. reduces LDL cholesterol by 43%,
while statins such as fluvastatin and
The focus on the risk of rhabdomyolysis an extra 6 percentage points. For
rosuvastatin are metabolized by someone with a baseline LDL
from grapefruit juice consumption with
CYP2C9 (Table 1) and pravastatin cholesterol of 4.8 mmol/L, these
statins ignores the greater benefits for
is metabolized enzymatically in the are equivalent to a 1.8-mmol/L
liver.6 This explains why grapefruit
the higher effective statin dose.
reduction (0.37  4.8) and a 2.1
juice interacts with atorvastatin, mmol/L reduction, respectively.
simvastatin, and lovastatin, but not The effect of a standard serving
with fluvastatin, rosuvastatin, or pravastatin.11 Removal of of grapefruit juice is to increase the effective dose of sim-
furanocoumarins from grapefruit juice eliminates the grape- vastatin or lovastatin by about 3.6-fold when given at the
fruit juice effect.18 same time as the statin, and by 1.9-fold when given 12 hours
earlier. Therefore, the effect of grapefruit juice if consumed
at the same time as taking simvastatin or lovastatin is to
reduce LDL cholesterol by an additional 11.1% [log(3.6)/
EFFECTS OF GRAPEFRUIT JUICE ON THE log(2)  6%], equivalent to a 0.53 mmol/L (11.1%  4.8
PHARMACOKINETICS OF STATINS mmol/L) reduction (see Table 2). The effect of grapefruit
A study19 showed that when 40 mg simvastatin was taken with juice if consumed 12 hours before taking simvastatin or
unusually large intakes of grapefruit juice (equivalent to 6 whole lovastatin is to reduce LDL cholesterol by an additional
grapefruits a day), the blood levels of the statin (expressed as the 5.6% [log(1.9)/log(2)  6%], equivalent to a 0.27-mmol/L
area under the curve [AUC] in a pharmacokinetic study) (5.6%  4.8 mmol/L) reduction (see Table 2).
increased by about 13.5-fold. However, another study20 A 1-mmol/L reduction in serum LDL cholesterol reduces the
examined the effect of a typical grapefruit juice intake (equiv- risk of ischemic heart disease (IHD) in a 60-year-old by 41%.21
alent to an 8-oz [240-mL] glass or 1 grapefruit per Using this, together with the absolute reduction in LDL shown
day) consumed at breakfast, and 40 mg simvastatin was taken at
the same time, as there was only a 3.6-fold increase in the AUC.
The grapefruit juice effect with statins has been shown to Table 1 Time to Maximum Concentration, Half Life, and
decrease to 10% of its maximum 24 hours after intake of Method of Metabolic Degradation According to Statin*
grapefruit juice, suggesting that the half-life of the grapefruit
Approx. Time to Maximum Half Life Metabolic
juice effect is between 7 and 8 hours, similar to that of Statin Concentration (Hours) (Hours) Degradation
CYP3A4.19 Therefore, it can be deduced that for statins that
have relatively short half-lives (eg, simvastatin or lova- Atorvastatin 2 23 CYP3A4
Lovastatin 3 3 CYP3A4
statin), grapefruit juice taken in the evening will have
Simvastatin 2 2 CYP3A4
approximately half the effect of grapefruit juice taken in the
Fluvastatin 1 1 CYP2C9
morning. The results from a study12 that observed a 1.9-fold Rosuvastatin 3 21 CYP2C9
increase in the AUC of lovastatin when grapefruit juice was Pravastatin 1 2 Sulphation
taken at breakfast and 40 mg of lovastatin in the evening are
*Adapted from Bellosta et al.6
consistent with this; they were approximately 50% lower
28
Table 2 Estimated Reduction in Serum LDL Cholesterol and Risk of Heart Attack According to Typical Grapefruit Juice Consumption and
Time of Consumption in Relation to Taking the Statin* [Grapefruit Juice Has No Effect on Pravastatin or Rosuvastatin]
% Reduction in Serum
Consumption of Grapefruit Effective Standard LDL Cholesterol
Juice in Relation to Taking Dose of Statin 37% þ[log(a)/log(2)  6%] b  4.8
the Statin (a) (b)
Not consumed 1 37%
12 hours before 1.9 43%
simvastatin (40 mg)
or lovastatin (40 mg)
At same time as 3.6 48%
simvastatin (40 mg)
or lovastatin (40 mg)
Any time with atorvastatin 1.8 42%
(10 mg)
LDL ¼ low-density lipoprotein.
*Estimated reductions for a 60-year-old man with a baseline serum LDL cholesterol of 4.8 mmol/L.
in Table 2, 10 mg atorvastatin, 40 mg simvastatin, or 40 mg
lovastatin reduces IHD risk by 61% (1-[1-0.41]1.8). Grapefruit
juice þ 40 mg simvastatin or 40 mg lovastatin reduces IHD risk
by 70% (1-[1-0.41]2.3), and grapefruit juice 12 hours before 40
mg simvastatin or 40 mg lovastatin reduces IHD risk by 66% (1-
[1-0.41]2.0). This is summarized in Table 2.
Risk of Rhabdomyolysis in Statin Users
The single serious and potentially fatal side effect of statin use
is rhabdomyolysis. A study published in 2006 examined this
risk using data from cohort studies, randomized trials, volun-
tary notifications to health agencies, and case reports.22 The
incidence of rhabdomyolysis for individuals on lovastatin,
simvastatin, and atorvastatin was about 4 per 100,000 person-
years, compared with a 1 per 100,000 person-years risk for
fluvastatin or pravastatin, which are less effective in lowering
LDL cholesterol. A nested case-control study on 29 cases of
rhabdomyolysis from a cohort of 315,562 simvastatin users
compared simvastatin 40 mg and 20 mg daily and reported
rates of rhabdomyolysis to be 11.5 (95% confidence interval,
7.1-17.5) and 2 (0.7-4.8) per 100,000 person-years, respec-
tively.23 The incidence of statin-induced rhabdomyolysis is so
rare that the increase in effective statin dose with concomitant
use of grapefruit juice would increase the risk by a small
amount e the magnitude of the increased risk is uncertain, but
on the basis of the increase in blood levels of the statin on its
metabolite, is unlikely to exceed 1-2 per 100,000 person years.
Prescribing Implications
The expected effect of grapefruit juice consumption is to
increase the reduction of LDL cholesterol by up to about 6
percentage points, with a similar reduction in the incidence of
IHD. It would be perverse to regard this enhanced efficacy as
an adverse effect. Even with the small risk of rhabdomyol-
ysis, there is a net health benefit. The counter argument that,
if it were intended to administer an increased dose of the drug
this should have been prescribed, is not persuasive because a
The American Journal of Medicine, Vol 129, No 1, January 2016
Absolute Reduction in Serum Estimated Reduction in
LDL Cholesterol (mmol/L) Ischemic Heart Disease Risk
1(10.41)c
(c) (d)
1.8 61%
2.0 66%
2.3 70%
2.0 66%
more practical approach would be to ask whether an indi-
vidual being prescribed a statin regularly drank grapefruit
juice and if the prescriber felt it was necessary, to prescribe a
lower dose. This is more considerate of the wishes of the
individual who may enjoy drinking grapefruit juice but who
requires statin therapy. In any event, doses of statins are not,
in practice, carefully titrated for individual patients.
The perception that grapefruit juice is contraindicated
when taking a statin is misleading, a conclusion derived from
pharmacokinetic studies that use unusually large amounts of
grapefruit juice. The view that grapefruit juice can enhance
the therapeutic benefit of drugs is already recognized in
cancer treatment,24 where the cost of the drug is substantial
and there is economic benefit in the enhancement. By
contrast, for statins the economic benefit is negligible, and the
utility is in accommodating the patient’s dietary preferences.
CONCLUSION
There is a well-characterized interaction between grapefruit
juice and certain statins. This interaction leads to the effective
dose of a statin being increased, with resulting benefits in
reducing LDL cholesterol and IHD. The risk of rhabdomyol-
ysis is much less in comparison, and overall, there is no need to
advise people on statins to avoid drinking grapefruit juice.
References
1. Simvastatin: updated advice on drug interactions: Medicines and Health-
care Products Regulatory Agency; 2012. Available at: https://www.gov.
uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions.
Accessed June 12, 2015.
2. U.S. Food and Drug Administration. Grapefruit juice and medicine may
not mix [updated January 20th 2015]. Available at: http://www.fda.gov/
ForConsumers/ConsumerUpdates/ucm292276.htm. Accessed June 12,
2015.
3. Pirmohamed M. Drug-grapefruit juice interactions: two mechanisms
are clear but individual responses vary. BMJ. 2013;346:f1.
4. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol
enhances the hemodynamic effects of felodipine. Clin Invest Med.
1989;12(6):357-362.
Lee et al Grapefruit Juice and Statins
5. Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions:
forbidden fruit or avoidable consequences? CMAJ. 2013;185(4):309-316.
6. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical
pharmacokinetics and drug interactions. Circulation. 2004;109(23
Suppl 1):III50-III57.
7. Ando H, Tsuruoka S, Yanagihara H, et al. Effects of grapefruit juice on
the pharmacokinetics of pitavastatin and atorvastatin. Br J Clin Phar-
macol. 2005;60(5):494-497.
8. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments
drug bioavailability—mechanism, extent and relevance. Eur J Clin
Nutr. 2004;58(1):1-9.
9. Guo LQ, Fukuda K, Ohta T, Yamazoe Y. Role of furanocoumarin
derivatives on grapefruit juice-mediated inhibition of human CYP3A
activity. Drug Metab Dispos. 2000;28(7):766-771.
10. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin inter-
action: effect on serum concentrations of simvastatin, simvastatin acid,
and HMG-CoA reductase inhibitors. Clin Pharmacol Ther. 1998;64(5):
477-483.
11. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum
concentrations of atorvastatin and has no effect on pravastatin. Clin
Pharmacol Ther. 1999;66(2):118-127.
12. Rogers JD, Zhao J, Liu L, et al. Grapefruit juice has minimal effects on
plasma concentrations of lovastatin-derived 3-hydroxy-3-methyl-
glutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther.
1999;66(4):358-366.
13. He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF.
Inactivation of cytochrome P450 3A4 by bergamottin, a component of
grapefruit juice. Chem Res Toxicol. 1998;11(4):252-259.
14. Lombaert GA, Siemens KH, Pellaers P, Mankotia M, Ng W.
Furanocoumarins in celery and parsnips: method and multiyear
Canadian survey. J AOAC Int. 2001;84(4):1135-1143.
29
15. Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al. Mechanisms
of enhanced oral availability of CYP3A4 substrates by grapefruit
constituents. Decreased enterocyte CYP3A4 concentration and
mechanism-based inactivation by furanocoumarins. Drug Metab
Dispos. 1997;25(11):1228-1233.
16. Sorokin AV, Duncan B, Panetta R, Thompson PD. Rhabdomyolysis
associated with pomegranate juice consumption. Am J Cardiol.
2006;98(5):705-706.
17. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases
felodipine oral availability in humans by decreasing intestinal CYP3A
protein expression. J Clin Invest. 1997;99(10):2545-2553.
18. Paine MF, Widmer WW, Hart HL, et al. A furanocoumarin-free grape-
fruit juice establishes furanocoumarins as the mediators of the grapefruit
juice-felodipine interaction. Am J Clin Nutr. 2006;83(5):1097-1105.
19. Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit
juice on the pharmacokinetics of the CYP3A4 substrate simvastatin.
Clin Pharmacol Ther. 2000;68(4):384-390.
20. Lilja JJ, Neuvonen M, Nevonen PJ. Effect of regular consumption of
grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin
Pharmacol. 2014;58:56-60.
21. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis. BMJ. 2003;326(7404):1423.
22. Law M, Rudnicka AR. Statin safety: a systematic review. Am J
Cardiol. 2006;97(8A):52C-60C.
23. Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdo-
myolysis: nested case-control study based on national health and drug
dispensing data. Int J Cardiol. 2014;174(1):83-89.
24. Cohen EE, Wu K, Hartford C, et al. Phase I studies of sirolimus alone
or in combination with pharmacokinetic modulators in advanced
cancer patients. Clin Cancer Res. 2012;18(17):4785-4793.