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The January 5th issue of the Medical Letter, a widely respected source of independent information about pharmaceuticals and dietary supplements, has a review of the increasingly researched problem of the interaction between grapefruit juice and many prescription and over-the-counter drugs. Like most interactions between chemicals in the body, this one involves the impairment, by grapefruit juice, of the body’s (intestine’s) ability to metabolize many drugs, leading to higher than expected...
The January 5th issue of the Medical Letter, a widely respected source of independent information about pharmaceuticals and dietary supplements, has a review of the increasingly researched problem of the interaction between grapefruit juice and many prescription and over-the-counter drugs. Like most interactions between chemicals in the body, this one involves the impairment, by grapefruit juice, of the body’s (intestine’s) ability to metabolize many drugs, leading to higher than expected — and sometimes dangerous — levels of these drugs. According to the Medical Letter, the enzyme inhibited by grapefruit juice, leading to the impairment of metabolizing drugs, “is involved in the metabolism of about half of all drugs currently prescribed.”
Addressing the issue of whether you can avoid this problem by drinking grapefruit juice at a time other than when you take your medicines, the article went on to say that, “because grapefruit juice is at least partly an irreversible inhibitor,...the activity of the enzyme does not immediately return to normal after the juice has moved through the intestine. Interactions with drugs, therefore, cannot be fully avoided by taking them at a different time. The recovery half-life... after a single glass of grapefruit juice appears to be about one day, and after 3 days little inhibitory effect remains... One glass a day for 3 days doubled serum concentrations of lovastatin (the cholesterol-lowering drug, MEVACOR).”
What You Can Do
The article recommends avoiding grapefruit juice or grapefruit if you are using any of the following drugs because they require careful control of blood concentrations: amiodarone (CORDARONE, and other generic versions), carbamazepine (TEGRETOL): and others), cyclosporine (SANDIMMUNE and others), sirolimus (RAPAMUNE) or tacrolimus (PROGRAF). Other citrus fruits, including pomelos and Seville oranges, which also contain the chemicals inhibiting drug metabolism, should also be avoided if using the above drugs.
The Medical Letter advises that if you are using any of the other drugs listed in the article, “limiting daily intake to one 8-oz glass of juice or one half of a fresh grapefruit would probably avoid any adverse drug interactions.”
The complete list discussed by the Medical Letter appears in the chart starting below.
When over-the-counter diet drugs containing phenylpropanolamine (PPA) were banned several years ago because of increased risk of hemorrhagic stroke, the immediate replacements were dietary supplements containing ephedra alkaloids. Now, as the demise of the equally if not more dangerous ephedra alkaloids approaches, the main substitute is citrus aurantium or Bitter Orange, one active ingredient in which is the sympathomimetic drug (stimulant) synephrine.
Like ephedrine alkaloids, Bitter Orange is usually sold in combination with caffeine or caffeine-like compounds that potentiate its adverse effects on the cardiovascular system, such as increasing blood pressure, pulse and the possibility of cardiac arrhythmias. In addition, bitter orange is used experimentally to inhibit intestinal cytochrome P450 (CYP) 3A4 — an enzyme responsible for the metabolism of a large proportion of drugs. Thus, like grapefruit juice, it can cause an alarming increase in the blood levels of many drugs.
Both bitter orange and grapefruit juice contain some of the same compounds that inhibit these drug-metabolizing intestinal enzymes (in addition to the stimulant in bitter orange — synephrine), resulting in higher blood levels of other drugs. Human studies have indeed documented that bitter orange does significantly inhibit the metabolism of drugs such as the calcium channel blocker felodipine (PLENDIL), prescribed for hypertension, and the widely used cough suppressant dextromethorphan (ROBITUSSIN DM). The maximum plasma concentrations of felodipine, in the presence of bitter orange, were increased an average of 61%. For dextromethorphan, bitter orange significantly increased the bioavailablity of the drug and the researchers concluded that bitter orange had “long-lasting inhibitory properties.” The inhibitory effects of grapefruit juice and bitter orange were similar for both drugs.
Thus, because of the 1994 Dietary Supplement Health and Education Act (DSHEA), when ephedra manufacturers decided to phase out this dangerous and uninsurable substance, they were able, with no hurdles in their way, to immediately substitute bitter orange for ephedra. There was no requirement to test for safety or effectiveness or to report adverse reactions to the FDA. How many deaths, strokes, heart attacks and other serious damage needs to occur in this country from bitter orange or other essentially unregulated dietary supplements before the congress wakes up and repeals or significantly modifies this dangerous law?
|
SOME DRUGS AFFECTED BY GRAPEFRUIT JUICE |
||
|---|---|---|
|
Albendazole (Albenza) |
Possible increased effect |
|
|
Amiodarone (Cordarone) |
Possible toxicity |
Avoid concurrent use |
|
Benzodiazepines |
Increased effect with triazolam, oral midazolam; theoretically alprazolam, diazepam also |
Avoid concurrent use |
|
Budesonide (Entocort EC) |
Possible toxicity |
Systemic exposure doubled |
|
Buspirone (BuSpar) |
Possible toxicity |
Avoid concurrent use |
|
Carbamazepine (Tegretol) |
Possible toxicity |
Monitor concentrations |
|
Cyclosporine (Sandimmune, Neoral) |
Possible toxicity |
Monitor concentrations |
|
Dextromethorphan |
Increased risk of toxicity |
Modest effect |
|
Diltiazem (Cardizem) |
Possible toxicity |
Modest effect |
|
Erythromycin |
Possible increased toxicity |
Modest effect |
|
Estrogens |
Increased ethinyl estradiol and 17®-estradiol effect |
|
|
Etoposide (VePesid) |
Possible decreased effect |
Avoid concurrent use |
|
Felodipine (Plendil) |
Possible toxicity |
Larger effect with multiple doses; amlodipine is minimally affected |
|
Fexofenadine (Allegra) |
Possible decreased effect |
Large amount; apple and orange juice had similar effect |
|
Fluoxetine (Prozac) |
Possible serotonin syndrome |
Single case report; patient also taking trazodone which could have contributed |
|
Fluvoxamine |
Possible increased toxicity |
Based on study in healthy subjects |
|
HMG-CoA reductase inhibitors |
Possible increased lovastatin, simvastatin or (less likely) atorvastatin toxicity |
Effect may last =24 hrs; unlikely with pravastatin, fluvastatin and rosuvastatin |
|
Indinavir (Crixivan) |
Possible decreased effect |
Conflicting results; clinical importance not established |
|
Itraconazole (Sporanox) |
Possible decreased effect |
Avoid concurrent use |
|
Lovastatin (Mevacor) |
See HMG-CoA reductase inhibitors |
|
|
Methylprednisolone (Medrol) |
Possible increased effects |
Large amounts |
|
Nicardipine (Cardene) |
Possible increased toxicity |
Little change in hemodynamic effect |
|
Nifedipine (Procardia) |
Increased risk of toxicity |
Avoid concurrent use |
|
Nimodipine (Nimotop) |
Possible toxicity |
Avoid concurrent use |
|
Nisoldipine (Sular) |
Possible increased toxicity |
Avoid concurrent use |
|
Praziquantel (Biltricide) |
Possible toxicity |
Based on study in healthy subjects |
|
Quinidine |
Possible toxicity |
Modest effect |
|
Saquinavir (Invirase; Fortovase) |
Increase in bioavailability |
Modest effect, clinical significance unknown |
|
Sertraline (Zoloft) |
Possible toxicity |
Clinical importance unclear |
|
Sildenafil (Viagra) |
Possible sildenafil toxicity; vardenafil (Levitra) and tadalafil (Cialis) may also interact |
Avoid concurrent use |
|
Simvastatin (Zocor) |
See HMG-CoA reductase inhibitors |
|
|
Sirolimus (Rapamune) |
Possible toxicity |
Avoid concurrent use |
|
Tacrolimus (Prograf) |
Possible toxicity |
Case report of dramatic increase in concentration after patient ate one pomelo; avoid concurrent use |
|
Theophylline |
Possible decreased effect |
Modest effect |
|
Verapamil (Calan) |
Possible increased toxicity |
Modest increase in verapamil serum concentrations |
|
Warfarin (Coumadin) |
Possible increased anticoagulant effect |
Single case report (1999); no effect seen in previous report of 10 patients on warfarin |
