Recent studies have shown that taking medication with grapefruit juice increases the concentration of many drugs in humans. This seems to be due to the ability of grapefruit juice to inhibit an enzyme system found in cells lining the small intestine. This happens to be the same enzyme system that metabolizes certain prescription drugs. Therefore, inhibition of this system can result in an increase in bioavailability and maximal plasma concentrations of these drugs. This can be a cause of concern because grapefruit juice can cause certain drugs to stay in the body longer at levels higher than normal. This can create many potential problems. Side effects of the drugs may be enhanced and serious toxicity can occur.
Various classes of prescription medications should not be taken at the same time with grapefruit juice. Such classes include some sedatives, antianxiety agents, calcium channel blockers, certain statins (for high cholesterol), and antidepressants. Drugs that have been found to have the most marked interaction with grapefruit juice are as follows: felodipine, nitrendipine, nisoldipine, and saquinavir. Less pronounced increases in concentration were found for nifedipine, nimodipine, verapamil, cyclosporin (an antirejection drug for transplant recipients), midazolam, triazolam, and terfenadine (an antihistamine). Grapefruit juice should also be avoided with certain antibiotics: erythromycin, azithromycin, and clarithromycin. These lists are by no means complete because many drugs have not been studied yet.
Methadone has been demonstrated to inhibit the same enzyme system as grapefruit juice. Caution should be exercised when utilizing this medication as well, especially with other drugs that are able to induce or inhibit this enzyme system, such as rifampicin, nifedipine, diazepam, and fluvoxamine.
The components of grapefruit juice that are responsible for interacting with these drugs have yet to be fully determined. However, nariginin, a bioflavenoid in grapefruit juice is suspected to be influencing drug metabolism.Furanocoumarins, also found in grapefruit juice, may even be more potent inhibitors than flavenoids. In any case, evaluating the need to avoid concomitant grapefruit juice intake or methadone with prescription medication is best done on an individual basis with your physician. (from http://www.headachedrugs.com/archives/grapefruit.html)
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INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS Interaction of Grapefruit Juice with Antihistamines The most significant interaction of grapefruit juice occurred with anithistamines. Do not take grapefruit juice if you are taking terfenadine (seldane) or astemizole (Hismanal) due to the possibility of fatal cardiac arrhythmias. Other non-sedating antihistamines are available which do not appear to interact with grapefruit juice. (e.g., loratidine (Claritin) cetirizine (Reactine) or fexofenadine (Allegra). In Australia, it is
routine practice to add auxiliary labelling to prescriptions for
terfenadine warning of grapefruit-juice drug interactions. In the
United States, the manufacturer of terfenadine has changed its
prescribing information to indicate that GJ should not be taken with
terfenadine. To study the effect of grapefruit juice on terfenadine 12 healthy subjects were given terfenadine 60 mg with either water or grapefruit juice, co-administered with terfenadine or delayed by 2 hours. Results:
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Lovastatin (Mevacor)
Kantola T et al. ( Clin Pharmacol Ther 1998; 63: 397-402) studied ten healthy subjects in an open randomized crossover trial to determine how grapefruit juice interacts with lovastatin. The subjects drank 200 mL double strength grapefruit juice or water for two days before being given a single 80 mg dose of lovastatin ( 2-4 times the usual dosage).
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Peak concentrations of lovastatin and lovastatin acid (an active metabolite) were increased on average 12-fold for lovastatin, and 4-fold for lovastatin acid. |
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The area under the curve (AUC) was increased 15-fold for lovastatin and 5-fold for lovastatin acid. |
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The half-life of lovastatin and lovastatin acid was not affected. |
The authors advised that co-administration of lovastatin with grapefruit juice be avoided.
To keep these results in perspective, the study employed double
strength grapefruit juice and higher than normal dosage of
lovastatin. However, a 15-fold increase in AUC and a 12-fold increase
in peak levels as a result of interaction with grapefruit juice should
be of serious concern.
A group of researchers from Merck (the manufacturer of Mevacor)
conducted their own research to determine the effect of grapefruit
juice on normal dosage of
lovastatin. Sixteen healthy subjects received either 8 ounces of
single-strength GJ or water with breakfast for 3 consecutive days. The
subjects then received a single 40mg dose of lovastatin in the evening
of the third day. The AUC and Cmax of all active HMG-CoA reductase
inhibitors increased by approximately 40% each in the GJ group. The AUC
and Cmax values for lovastatin approximately doubled in the GJ
patients, and lovastatin acid AUC and Cmax increased 1.6 fold. The
authors explained the lower interaction in their experiment by the fact
that they used a normal dose of lovastatin (40mg daily in the evening)
and a normal amount of grapefruit juice (one regular strength glass
daily with breakfast). They concluded that daily consumption of a glass
of regular-strength GJ has a minimal effect on plasma concentrations of
HMG-CoA reductase inhibitors after a 40mg evening dose of
lovastatin.
Simvastatin (Zocor)
Ten healthy volunteers received either 200 mL water or double strength grapefruit juice three times daily for 2 days before receiving a single 60mg dose of simvastatin (Note: 3-6x the usual dosage), in a randomized crossover fashion. Lilja, JJ, Kivisto KT, Neovonen PJ. ( Clin Pharmacol Ther 1998; 64: 477-83), who conducted the clinical trial reported that grapefruit juice increased:
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The simvastatin AUC by 1513% |
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The Cmax (Maximum concentration) by 842% |
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Simvastatin acid AUC by 577% |
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Cmax by 555% |
Time to peak concentration of simvastatin was increased from 1 hour to 2.5 hours.
Again, to keep things in perspective, double-strength grapefruit juice was used, and a higher than usual dose of simvastatin was used in the study. But the grapefruit juice interaction is quite dramatic on the simvastatin blood levels. The authors recommended that you do not use grapefruit juice and simvastatin simultaneously, or to use substantially lower dosage of simvastatin when used in combination with grapefruit juice.
Atorvastatin (Lipitor)
Lilja JJ, and co-investigators ( Clin Pharmacol Ther 1999; 66: 118-27) reported the results of clinical trials conducted to determine how grapefruit juice intracts with atorvastatin and provastatin.
Twelve healthy volunteers received either 200 mL water or double strength grapefruit juice three times daily for two days before receiving a single 40 mg dose of atorvastatin with either 200 mL water or grapefruit juice in a randomized crossover fashion. Subjects took an additional 200 mL water or grapefruit juice three times daily on day 4 and 5 as well.
Grapefruit juice increased:
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The atorvastatin acid AUC by 2.5 fold |
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The peak concentration of atorvastatin acid was not affected |
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Time to peak concentration by 200% |
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Half-life by 70% |
Atorvastatin has two active metabolites: atorvastatin lactone and 2-hydroxyatorvastatin acid which were also affected by
GJ, with the AUC of active and total HMG-CoA reductase inhibitors being increased 1.3 fold and 1.5 fold respectively.
Grapefruit juice interacts with atorvastatin (lipitor) by a much
less extent
than its effect on lovastatin and simvastatin. The authors concluded
that grapefruit juice, at least in large amounts, should not be used
concomitantly with
atorvastatin, or the dosage of atorvastatin should be reduced
accordingly.
Pravastatin (Pravachol)
Eleven healthy volunteers
received either 200 mL water or double strength grapefruit juice three
times daily for two days before receiving a single 40mg dose of
pravastatin with either 200 mL water or grapefruit juice in a
randomized crossover fashion.
Grapefruit juice had no significant effects on the pharmacokinetics of
pravastatin, other than the tmax of active HMG Co-A reductase
inhibitors was significantly prolonged from 1 hour to 2 hours. The
authors concluded that pravastatin is not susceptible to interaction
with
grapefruit juice and other CYP3A4 inhibitors.
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INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS Grapefruit Juice and Psychiatric Medications Several psychiatric medications are affected by the metabolism of cytochrome p450 isoenzyme 3A4 (CYP3A4). The bioavailability was affected. A significant increase in pharmacodynamic effects, such as prolonged reaction times was also observed. The interactions could have important implications in patients with other conditions that might increase benzodiazepine bioavailability (e.g. advanced age, liver cirrhosis, concurrent use of other medications that inhibit cytochrome P450). These patients should be observed for increased sedation. Triazolam (Halcion) Diazepam (Valium) Eight healthy subjects were given diazepam 5mg orally with either 250 mL water or grapefruit juice. The mean AUC of diazepam was increased 3.2-fold and the peak concentration was increased 1.5-fold by the grapefruit juice. Grapefruit juice postponed the time to reach peak concentration of diazepam from 1.5 hours to 2.1 hours. (Reference: Ozdemir M, Aktan Y, Boydag BS., Eur J Drug Metab Pharmacokinet 1998 Jan-Mar;23(1):55-9.) Alprazolam (Xanax) Alprazolam is a substrate
of CYP3A4, and may be subject to similar increases in AUC and clinical
effects as seen with the other CYP3A4-metabolized
benzodiazepines. Grapefruit Juice and Calcium Channel Blockers Several studies recorded the effect of grapefruit juice on calcium channel blockers. The grapefruit juice seems to affect mainly the dihydropyridine family of calcium-channel blockers. Most studies used healthy persons. It is expected that people with existing hypertension or cardiac condition may be more adversely affected by the grapefruit juice interaction. The following is a summary of clinical findings on how grapefruit juice affects the bio-availability and side reactions of calcium channel blockers. Felodipine (Plendil, Renedil) Felodipine was given with double-strength grapefruit juice to six hypertensive patients. Results:
Nifedipine (Adalat, Procardia) Patients taking nifedipine experienced an increase in AUC by 34%. Amlodipine (Norvasc) In 12 healthy subjects amlodipine AUC was increased by 16% and patients experienced a slight reduction in diastolic blood pressure when amlodipine was given with single-strength grapefruit juice. Nitrendipine In nine patients, nitrendipine AUC was increased by 106% when given with grapefruit juice. Nisoldipine In 12 patients, nisoldipine AUC was increased by 98% when given with grapefruit juice, and peak concentrations were increased by 406%. There was marked variation within individuals as to how they reacted to the grapefruit juice. Only minor effects on blood pressure and heart rate were noted. Verapamil (Isoptin, Calan) In a crossover study of 24 volunteers, verapamil and norverapamil AUCs were increased 43% and 28%, while the maximum plasma concentration of verapamil and norverapamil were increased 60% and 32%. Four subjects in the grapefruit juice-verapamil phase had a PR interval prolongation to greater than 0.24 seconds. Diltiazem (Cardizem, Tiazac) Nine healthy male subjects received 120mg diltiazem with either 200 mL of water or single-strength grapefruit juice. Results:
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