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Drug - Grapefruit Interactions
(Review)
This document Copyright © 2003
D.McAuley, GlobalRPh Inc. All Rights Reserved.
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Background information:
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| Grapefruit juice is a potent inhibitor of the intestinal
cytochrome P-450 3A4 system (specifically: CYP3A4 - mediated drug
metabolism) which is responsible for the first-pass
metabolism of many medications. This interaction can lead to
increases in bioavailability and corresponding increases in
serum drug levels.
In many cases, the increased serum drug levels can
produce some readily observable symptoms. Here are a few
examples of adverse effects that are possible when
the following medications are taken concurrently with
grapefruit. (1) Excessive
sedation: benzodiazepines. (2) Increased risk of
rhabdomyolyis: HMG-CoA reductase inhibitors (statins)-- there
are some exceptions.
(3) Symptomatic hypotension: dihydropyridine calcium
antagonists (some exceptions exist). (4) QT interval prolongation: astemizole, cisapride,
pimozide, terfenadine. "Drug interactions may be most apparent when patients are
stabilized on the affected drug and the CYP3A4 inhibitor is then added to the regimen."
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There may be some pharmacological advantages to
this interaction. If the interaction is taken into account during the
initialization of drug therapy it is possible to decrease drug
dosages. This concept can be applied to cyclosporine therapy. If a
patient regularly consumes grapefruit, lower dosages of
cyclosporine will be required, which will lead to lower drug
costs.
Grapefruit juice is not the only inhibitor of this enzyme
system. Other drugs which have a
similar effect include: clarithromycin (Biaxin ®),
erythromycin (E-Mycin ®, others), itraconazole (Sporonox ®),
ketoconazole (Nizoril
®), nefazodone (Serzone ®), and ritonavir (Norvir ®). |
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Drugs which may exhibit increased serum
concentrations based on this interaction |
| amiodarone |
astemizole |
alprazolam
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atorvastatin
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| benzodiazepines |
buspirone
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carbamazepine
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carvedilol
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| cerivastatin
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cilostazol
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clarithromycin |
Clomipramine |
| codeine
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cyclosporine |
dapsone |
dextromethorphan |
| diazepam
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diltiazem
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estrogens |
erythromycin |
| felodipine
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fentanyl |
finasteride |
haloperidol
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| indinavir |
lercanidipine |
lidocaine |
lovastatin
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| midazolam
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methadone |
nelfinavir
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nifedipine |
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nicardipine
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nimodipine |
nisoldipine |
nitrendipine |
| ondansetron
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paclitaxel |
progestins |
progesterone |
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quinidine
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ritonavir |
salmeterol |
saquinavir |
| simvastatin
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tacrolimus |
trazodone |
triazolam |
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vincristine
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zaleplon |
zolpidem |
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Note:
there may be omissions on this list. Absence of a drug
does not necessarily indicate that the drug lacks this potential
interaction.
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References:
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1.
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Bailey DG, Dresser GK. Grapefruit juice-lovastatin interaction.
Clin Pharmacol Ther. 2000 Jun;67(6):690
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2.
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Bistrup C, Nielsen FT, Jeppesen UE, Dieperink H. Effect of grapefruit juice on Sandimmun Neoral absorption among stable
renal allograft recipients. Nephrol Dial Transplant. 2001 Feb;16(2):373-7.
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3.
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Bramer SL, Brisson J, Corey AE. Effect of multiple cilostazol doses on single dose lovastatin
pharmacokinetics in healthy volunteers.
Clin Pharmacokinet. 1999;37 Suppl 2:69-77.
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| 4. |
Damkier P, Hansen LL, Brosen K. Effect of
diclofenac, disulfiram, itraconazole, grapefruit juice and
erythromycin on the pharmacokinetics of quinidine.
Br J Clin Pharmacol. 1999 Dec;48(6):829-38. |
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5.
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Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of
cytochrome P450 3A4 inhibition.
Clin Pharmacokinet. 2000 Jan;38(1):41-57.
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6.
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Dresser GK, Bailey DG, Carruthers SG. Grapefruit
juice--felodipine interaction in the elderly.
Clin Pharmacol Ther. 2000 Jul;68(1):28-34.
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| 7. |
Eagling VA, Profit L, Back DJ. Inhibition of the CYP3A4-mediated metabolism and
P-glycoprotein-mediated
transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice
components.
Br J Clin Pharmacol. 1999 Oct;48(4):543-52. |
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8.
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Evans AM. Influence of dietary components on the gastrointestinal metabolism and
transport of drugs
Ther Drug Monit. 2000 Feb;22(1):131-6.
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9.
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Fukuda K, Guo L, Ohashi N, Yoshikawa M, Yamazoe Y. Amounts and variation in grapefruit juice of the main components
causing grapefruit-drug interaction.
J Chromatogr B Biomed Sci Appl. 2000 May 12;741(2):195-203.
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10.
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Fuhr U. [Clinically significant" new drug interactions].
Med Klin. 2000 May;95(1 Spec No):18-22.
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11.
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Fuhr U, Maier-Bruggemann A, Blume H, Muck W, Unger S, Kuhlmann J,
Huschka C, Zaigler M, Rietbrock S, Staib AH. Grapefruit juice increases oral nimodipine
bioavailability. Int J Clin Pharmacol Ther. 1998 Mar;36(3):126-32.
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12.
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Garg SK, Kumar N, Bhargava VK, Prabhakar SK. Effect of grapefruit juice on carbamazepine bioavailability in patients
with epilepsy.
Clin Pharmacol Ther. 1998 Sep;64(3):286-8.
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| 13.
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Kanazawa S, Ohkubo
T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of
erythromycin. Eur J Clin Pharmacol. 2001 Jan-Feb;56(11):799-803.
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14.
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Kane GC, Lipsky JJ. Drug-grapefruit juice interactions.
Mayo Clin Proc. 2000 Sep;75(9):933-42.
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15.
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Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC. The effects of grapefruit juice on sertraline metabolism: an in vitro
and in vivo study.
Clin Ther. 1999 Nov;21(11):1890-9.
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16.
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Lilja JJ, Kivisto KT,
Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has
no effect on pravastatin.
Clin Pharmacol Ther. 1999 Aug;66(2):118-27.
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17.
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Lilja JJ, Kivisto KT, Backman
JT, Lamberg TS, Neuvonen PJ. Grapefruit juice substantially increases plasma concentrations of
buspirone.
Clin Pharmacol Ther. 1998 Dec;64(6):655-60.
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18.
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Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the
CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000 Oct;68(4):384-90.
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19.
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Lilja JJ, Kivisto KT, Backman JT, Neuvonen PJ. Effect of grapefruit juice dose on grapefruit
juice-triazolam
interaction: repeated consumption prolongs triazolam half-life.
Eur J Clin Pharmacol. 2000 Aug;56(5):411-5.
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20.
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Libersa CC, Brique SA, Motte KB, Caron JF, Guedon-Moreau LM,
Humbert L, Vincent A, Devos P, Lhermitte MA. Dramatic inhibition of amiodarone metabolism induced by grapefruit
juice.
Br J Clin Pharmacol. 2000 Apr;49(4):373-8.
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21.
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Mitsunaga Y, Takanaga H, Matsuo H, Naito M, Tsuruo T, Ohtani H,
Sawada Y. Effect of bioflavonoids on vincristine transport across blood-brain
barrier.
Eur J Pharmacol. 2000 May 3;395(3):193-201.
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22.
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Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A. Interaction between grapefruit juice and diazepam in humans.
Eur J Drug Metab Pharmacokinet. 1998 Jan-Mar;23(1):55-9.
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23.
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Singh BN. Effects of food on clinical pharmacokinetics.
Clin Pharmacokinet. 1999 Sep;37(3):213-55. Review.
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| 24. |
Zhang H, Wong CW, Coville PF, Wanwimolruk S.
Effect of the grapefruit flavonoid naringin on pharmacokinetics of
quinine in rats. Drug Metabol Drug Interact. 2000;17(1-4):351-63.
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© D.McAuley, GlobalRPH.com
2001
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