UKMi QA 87.1
Is there an interaction between grapefruit juice and statins?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date Prepared: 28th February 2012
Background
Grapefruit juice has been reported to interact with a variety of cardiovascular medicines including
some of the statins. The mechanism of this interaction is thought to be inhibition of the cytochrome
P450 (CYP) 3A4 enzyme. The active constituent of grapefruit juice is likely to be a furanocoumarin,
which binds to CYP3A4 and inactivates it. This interaction has been reported to occur even after
consuming just 200ml of grapefruit juice. As it can take some time for enzyme regeneration to occur,
inhibition can persist for up to 72 hours. When grapefruit juice is consumed several times a day on a
chronic basis, a cumulative inhibitory effect on intestinal CYP3A4 and an enhanced magnitude of drug
interaction is expected. Similarly, high intake of juice may also inhibit hepatic CYP3A4 and lead to
prolongation of the drug elimination half-life. An interaction is likely, whatever the source of the juice
i.e. fresh grapefruit and grapefruit juices including fresh, frozen or diluted from concentrate (1).
Answer
Simvastatin and atorvastatin are metabolised by CYP3A4 and co-administration with grapefruit juice
may increase levels of these drugs, and thus increase the risk of dose related side effects, including
myopathy and rhabdomyolysis. It is recommended that grapefruit juice should be avoided altogether in
users of simvastatin as even modest amounts can increase drug levels. The CSM recommended in
2004 that caution should be exercised when combining atorvastatin with any CYP3A4 inhibitor,
especially at high doses, and patients should avoid drinking large quantities of grapefruit juice (2). This
advice was updated by the MHRA in January 2008 to not only recommend that intake be limited to
very small quantities, though no definitive amount was specified, but also that avoidance altogether
may be advisable. The advice for users of simvastatin to avoid grapefruit juice remains unchanged (3).
Simvastatin
Lilja et al, have conducted several pharmacokinetic studies involving grapefruit juice and simvastatin
(4-6). The studies noted that grapefruit juice increased plasma levels of simvastatin and its metabolite
simvastatin acid by 2 to 12 fold, and 2 to 7 fold, respectively. Bioavailability was also similarly
increased, 2 to 16 fold and 2 to 7 fold, respectively.
A case of simvastatin-associated rhabdomyolysis possibly linked to grapefruit consumption, has been
reported in 'Neurology.' The case was a 40-year-old woman who was admitted to hospital with lower
extremity weakness. She reported slight muscle weakness and myalgia, which had appeared 10 days
ago. She had been taking simvastatin for familial hypercholesterolaemia for 2 years, and had had a
dose increase 6 months previously from 40mg to 80mg daily. Blood tests indicated rhabdomyolysis
and, given the patient's medication history, the researcher believed it was related to simvastatin. After
discontinuation of the drug and vigorous fluid replacement, the patient's condition improved and she
was discharged from hospital on day 6. When the patient was questioned about any recent triggers,
she mentioned eating one grapefruit every day for the 2 weeks before admission (7).
The SPC for Zocor™ (simvastatin) recommends that intake of grapefruit juice during treatment with
simvastatin should be avoided (8).
Atorvastatin
The SPC notes that intake of one 240 ml glass of grapefruit juice resulted in a 1.4 fold increase in
atorvastatin AUC and a 1.2 fold decrease in AUC of the active orthohydroxy metabolite. However,
larger quantities of grapefruit juice (over 1.2L daily for 5 days) increased AUC of atorvastatin 2.5 fold
and AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) 1.3 fold*. From these
data, the SPC states that the concomitant intake of large quantities of grapefruit juice and atorvastatin
is not recommended (9).
Lilja et al have also carried out a pharmakokinetic study examining the concomitant administration of
grapefruit juice with atorvastatin and pravastatin. Grapefruit juice increased the bioavailability of
atorvastatin and its metabolite atorvastatin lactone approximately 3 fold, but did not have a significant
effect on the pharmakokinetics of pravastatin (10).
A Japanese study evaluating the effects of grapefruit juice on atorvastatin, reported a mean 1.8 fold
increase in the AUC of the active acid form, atorvastatin acid (11).
A prospective open label randomised study has reported that “a reduction of atorvastatin dosage when
moderate amounts of GFJ are co-ingested does not appear to be necessary.” This study in patients on
treatment with atorvastatin assessed whether “customary” exposure to grapefruit juice (GFJ) altered
serum concentrations, effectiveness, and potential adverse effects. Patients on atorvastatin (10, 20 or
40mg day) at a stable dose received 300ml day of 100% GFJ for 90 days. One cohort (arm A, n= 60)
continued on current dose of atorvastatin; the second cohort (arm B, n= 70) reduced the daily dose by
50%. Serum atorvastatin, lipid profile, liver functions, and creatine phosphokinase (CPK) were
measured at baseline and at 30, 60, and 90 days after starting GFJ. In Arm A patients, co-ingestion of
GFJ elevated serum atorvastatin by 19% to 26% compared with baseline. Changes in lipid profile
relative to baseline were negligible and there were no adverse effects on liver function tests or CPK. In
arm B patients, serum atorvastatin declined by 12% to 25% compared to baseline, with a small
unfavourable effect in serum lipid profile. There were no adverse effects on liver function tests or CPK
(12).
Other statins
For other statins, the interaction is not clinically significant because fluvastatin is metabolised by a
different CYP450 enzyme (CYP2C9) whilst pravastatin and rosuvastatin are not substantially
metabolised by CYP450 (2).
See appendix for further details of the pharnacokinetic studies.
Summary

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Grapefruit juice can increase plasma levels of simvastatin and atorvastatin.
The concomitant administration of grapefruit juice and simvastatin should be avoided.
The MHRA in 2008 recommended that the intake of grapefruit juice in patients on atorvastatin be
limited to very small quantities (or avoided altogether) but the actual quantity had not been
defined. Since then, a three month clinical study in hyperlipidaemic patients reported that the
addition of daily grapefruit juice in typical quantities (300ml) slightly elevated serum atorvastatin
concentrations, but had no meaningful effect on the serum lipid profile, and caused no detectable
adverse liver or muscle effects.
An interaction has not been reported between grapefruit juice and other statins licensed in the UK,
as pravastatin and rosuvastatin are not substantially metabolised by CYP450, and fluvastatin is
metabolised by a different CYP450 enzyme (CYP2C9).
Limitations
There are limited patient data from one study and a case report; all other data come from
pharmacokinetic studies in a handful of healthy volunteers, and showed considerable inter-individual
variation in the statin-grapefruit juice interaction, thus making it difficult to predict the quantitative
effects of grapefruit juice on an individual basis.
*The March 2005 SPC for Lipitor stated 1.3 fold increase but this figure no longer in current SPC (December 2011) and Pfizer is
in process of clarifying if this figure was intended to be omitted.
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References
1
Adis International. Avoid even normal consumption of grapefruit juice if potential interaction
with oral cardiovascular drugs. Drugs Ther Persp 2005; 21 (9): 21- 24.
2 CSM. Statins and Cytochrome P450 interactions. Current Problems in Pharmacovigilance
2004; 30: 1-2.
3 MHRA. Drug Safety Update January 2008; Volume 1, Issue 6,
http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON2033505
4 Lilja, JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice- simvastatin interaction: effect on serum
concentrations of simvastatin, simvastatin acid and HMG-CoA reductase inhibitors. Clin
Pharmacol Ther 1998; 64: 477-483.
5 Lilja, JJ, Kivisto KT, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the
pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004; 58: 56-60.
6 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: 384390.
7 Dreier JP, Endres M. Statin- associated rhabdomyolysis triggered by grapefruit consumption.
Neurology 2004; 62: 670.
8 Summary of Product Characteristics - Zocor. MSD, last updated Sept 2005
9 Summary of Product Characteristics – Lipitor. Pfizer Ltd, last updated March 2005
10 Lilja, JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of
atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118-127.
11 Ando et al. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin.
Br J Clin Pharmacol 2005; 60: 494-497
12 Reddy P, Ellington D. Zhu Y, et al. Serum concentrations and clinical effects of atorvastatin in
patients taking grapefruit juice daily Br J Clin Pharmacol 2011; 72: 434-441
Appendix 1:
Summary of pharmacokinetic studies:
SIMVASTATIN
Study
Pt nos
Liquid
Cmax
(mean)
AUC (mean)
Comment
Randomised
crossover 2
phase study of
SV over 3 days,
with 2 week
interval
between
crossover (4)
Randomised
crossover 2
phase study of
SV over 3 days
with 2 week
interval
between
crossover (5)
10 healthy
volunteers
200ml liquid (DSGJ or
H2O) for 2 days then SV
60mg + 200ml liquid on
day 3 followed by 200ml
½ and 1½ hour later
SV
 9.4 fold
(5.1- 31.4,
p < 0.01)
SVA
 7 fold (1.431.4, p<0.01)
SV
 16 fold (937.7, p<0.05)
SVA
 7 fold (1.831.4, p<0.01)
Considerable interindividual variation.
Concomitant use
GJ and at least
high dose SV
should be avoided
10 healthy
volunteers
200ml liquid (NSGJ or
H2O) for 2 days then SV
40mg + 200ml liquid on
day 3
SV
 3.9 fold
(2.3- 9.3,
p < 0.001)
SVA
 4.3 fold
(2.7- 7.7,
p < 0.001)
SV
 3.6 fold
(1.8- 6.0,
p < 0.001)
SVA
3.3 fold
(2.5-5.6,
p < 0.001)
Non
randomised
crossover 3
phase study of
SV over 5 days
with 2 week
interval
between
crossover (6)
10 healthy
volunteers
Phase 1:
SV 40mg + 200ml H2O
Concomitant
admin
SV  12 fold,
p < 0.001),
SVA
 5 fold,
p < 0.001)
24 hrs after
last dose
juice
SV  2.4 fold,
p < 0.01),
SVA
 1.7 fold,
p < 0.01)
3 days after
last dose
juice
SV  1.5 fold,
p=0.12), no
diff in SVA
7 days after
last dose
juice
No difference
in SV and
SVA
Concomitant
admin
SV  13.5
fold,
p <0.001),
SVA
 4.5 fold,
p < 0.001)
24 hrs after
last dose
juice
SV  2.1 fold,
p < 0.001),
SVA
 1.7 fold,
p < 0.01)
3 days after
last dose
juice
SV  1.4 fold,
p =0.09); no
diff in SVA
7 days after
last dose
juice
No difference
in SV and
SVA
Considerable interindividual variation.
Even small
amounts contain
sufficient active
ingredients to
inhibit considerably
1st pass
metabolism
Considerable interindividual variation.
ATA- not
significantly
changed
ATL  2.6 fold
(p <0.01)
ATA  2.5
fold (1.7 5.7,p < 0.01)
ATL  3.3
fold
(p < 0.01)
ATA  1.7 fold
(p = 0.09)
ATL not
significantly
changed
ATA  1.83
fold
(p < 0.05)
ATL not
significantly
changed
Phase 2:
DSGJ 200ml tds for 2
days then SV 40mg +
200ml DSGJ on day
3+another 200ml DSGJ
½ and 1½ hr later then
2nd dose SV 40mg +
H20 three days later.
Phase 3:
DSGJ tds for 3 days
then SV 40mg + H20 on
dy 4 then another dose
SV 40 mg + H20 after 7
dys
ATORVASTATIN
Randomised
12 healthy
crossover 2
volunteers
phase study of
AT (10)
Randomised, 2
phase
crossover study
(11)
8 healthy
volunteers
200ml liquid (DSGJ or
H2O) for 2 days then AT
40mg + 200ml liquid on
day 3 followed by 200ml
½ and 1½ hours later
then 200ml liquid tds on
day 4 and 5
250ml liquid (NSGJ or
H2O) tds for 3 days then
on day 4, AT 20mg with
250ml GJ or H2O
followed by same liquids
at 12.00h and 20.00h.
Interaction potential
dissipates within 3
to 7 days after last
dose GJ
 half life ATA
(p < 0.01) and ATL
(p < 0.05)
Large amount GJ
should be avoided
in patients on ATA
or  dose AT
Considerable interindividual variation.
Key: GJ- grapefruit juice, DB- double strength, NS- normal strength, H2O- water, SV- simvastatin, SVAsimvastatin acid, AT- atorvastatin, ATA - atorvastatin acid, ATL- atorvastatin lactone
Quality Assurance
Prepared by
Yuet Wan, Regional Medicines Information, London and South-East, Guy’s Hospital
Contact
yuet.wan@gstt.nhs.uk
Date Prepared
Dec 2005 (updated May 2008 and Feb 2012)
Checked by
David Erskine, Director, Regional Medicines Information, London and South-East, Guy’s Hospital
Date of check
Feb 2012
Search strategy (2012)
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EMC
MHRA
Pfizer
EMBASE; exp GRAPEFRUIT EXTRACT/ OR exp GRAPEFRUIT JUICE/ OR exp
GRAPEFRUIT/; + exp HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE
INHIBITOR/; [Limit to: Publication Year 2008-Current and Human and English Language]
MEDLINE; exp CITRUS PARADISI/ + [exp HYDROXYMETHYLGLUTARYL-COA
REDUCTASE INHIBITORS/ or [atorvastatin.ti,ab or rosuvastatin.ti,ab or fluvastatin.ti,ab];
[Limit to: Publication Year 2008-Current and Humans and English Language]
Search strategy (2008)
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EMBASE 1996 to date: Hydroxymethylglutaryl−Coenzyme−A−Reductase−Inhibitor#.DE. +
[Grapefruit#.W..DE. OR Grapefruit−Juice#.DE.]: YEAR=2008 OR YEAR=2007 OR
YEAR=2006
MEDLINE −1996 to date: [Hydroxymethylglutaryl−Coa−Reductase−Inhibitors#.DE. or
atorvastatin or rosuvastatin] + Citrus−Paradisi#.DE: YEAR=2008 OR YEAR=2007 OR
YEAR=2006
MICROMEDEX Healthcare Series. Copyright © 1974-2008 Thomson Healthcare.
MHRA: Drug Safety Update
Search strategy (2006)
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Embase 1974 to date “[Grapefruit or Grapefruit-Juice] + Hydroxymethylglutaryl-Coenzyme-AReductase- Inhibitors “)
Medline 1996 to date “[Hydroxymethylglutaryl-Coa- Reductase- Inhibitors or atorvastatin or
rosuvastatin] + Citrus-Paradisi”)
Pharmline (“HMG-COA reductase inhibitors + grapefruits”)
EMC website for SPCs of statins licensed in UK (http://www.medicines.org.uk)
MHRA website for Current Problems in Pharmacovigilance
(http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=368); search
“grapefruit”
MICROMEDEX Healthcare Series Vol. 127 expires 3/2006 (search: simvastatin, atorvastatin)
Stockley’s Drug Interactions 6th ed. Pharmaceutical Press 2002 (grapefruit interactions: only
list details atorvastatin and pravastatin).