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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: 
         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." 5  
 


       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 ®). 



Drugs which may exhibit increased serum concentrations based on this interaction
amiodarone astemizole alprazolam atorvastatin
benzodiazepines  buspirone carbamazepine carvedilol
cerivastatin cilostazol  clarithromycin Clomipramine 
codeine cyclosporine  dapsone dextromethorphan
diazepam diltiazem estrogens erythromycin
felodipine fentanyl finasteride haloperidol
indinavir lercanidipine lidocaine lovastatin
midazolam methadone nelfinavir nifedipine
nicardipine nimodipine nisoldipine nitrendipine
ondansetron paclitaxel progestins progesterone
quinidine ritonavir salmeterol saquinavir
simvastatin tacrolimus trazodone triazolam
vincristine zaleplon zolpidem  


Note: there may be omissions on this list. Absence of a drug
does not necessarily indicate that the drug lacks this potential
interaction. 

 

References:
1.
Bailey DG, Dresser GK. Grapefruit juice-lovastatin interaction. Clin Pharmacol Ther. 2000 Jun;67(6):690
2.
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.
3.
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.
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.
5.
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.
6.
Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice--felodipine interaction in the elderly. Clin Pharmacol Ther. 2000 Jul;68(1):28-34.
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.
8.
 Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs Ther Drug Monit. 2000 Feb;22(1):131-6.
9.
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.
10.
Fuhr U. [Clinically significant" new drug interactions]. Med Klin. 2000 May;95(1 Spec No):18-22.
11.
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.
12.
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.
13. 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.
14.
Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000 Sep;75(9):933-42.
15.
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.
16. 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.
17. 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.
18.
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.
19.
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.
20.
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.
21.
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.
22.
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.
23.
Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet. 1999 Sep;37(3):213-55. Review.
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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