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Food–Drug Interactions

Which Ones Really Matter?

Darrell Hulisz, RPh, PharmD
Associate Professor of Family Medicine
Case Western Reserve University School of Medicine
Associate Clinical Professor of Pharmacy Practice
Ohio Northern University College of Pharmacy

Justin Jakab
Pharmacy Intern, University Family Medicine
Foundation, Cleveland, Ohio

3/21/2007

US Pharm. 2007;32(3)93-98.

Perhaps the most common question patients ask about their medication, aside from "Why does this medication cost so much?" is, "Should I take this with or without food?" In most cases, upon looking in the package insert or drug information resource, the pharmacist discovers that most drugs in question may be administered without regard to meals. However, some food products are fortified with vitamins and/or minerals that can interact with certain drugs. Therefore, the more appropriate question to ask is, "Which foods should I avoid taking with my medications?" Furthermore, many patients consume mega-vitamins and supplements with known drug interactions, yet they are often unaware of these interactions. The purpose of this article is to equip pharmacists with a better understanding of drug–food interactions. This article differs from traditional reviews on this topic because the food substance is categorized individually, with the interacting drugs discussed under each heading. While there are hundreds of drug–nutrient interactions reported in the literature, the aim here is to focus on those that are more common and clinically significant.

Grapefruit Juice

One of the most well known food–drug interactions is grapefruit juice and the HMG-CoA reductase inhibitors, more commonly known as statins. Grapefruit juice, in large quantities (32 oz. or more per day), can inhibit the cytochrome P450 3A4 (CYP3A4) enzyme and increase blood levels of drugs metabolized by this pathway, such as certain statin drugs.1,2 Note that this interaction applies to grapefruit juice, not the whole fruit itself. Furthermore, not all statins exhibit this interaction: Only atorvastatin (Lipitor), simvastatin (Zocor), and lovastatin (Mevacor) are metabolized by the CYP3A4 isoform. Of these three statins, atorvastatin is least affected by grapefruit juice. Thus, the other statins, namely rosuvastatin (Crestor), pravastatin (Pravachol), and fluvastatin (Lescol), may be acceptable alternatives for patients who regularly consume large amounts of grapefruit juice.3

Underlying this interaction is the ability of some constituents of grapefruit juice to inhibit CYP3A4 in the intestine, thereby reducing the metabolism of the statins and increasing the drug's bioavailability. Thus, when large amounts of grapefruit juice are consumed in combination with these drugs, patients are at an increased risk of statin-related side effects, most notably, muscle toxicity, which may manifest as myalgia, myopathy, or rhabdomyolysis.

While the statins receive the most public attention for their interaction with grapefruit juice, other drugs exhibit this same interaction. Calcium channel blockers are popular drugs that interact with grapefruit juice. All of the dihydropyridine calcium–blocking drugs, such as amlodipine (Norvasc), nifedipine (Procardia), and nicardipine (Cardene), as well as the non-dihydropyridine agent verapamil (Calan), interact with grapefruit juice.2 The calcium antagonist that is the most affected by the fruit juice is felodipine (Plendil), demonstrating as high as a 200% increase in the area under the curve (AUC) with coadministration. Diltiazem (Cardizem), although a substrate for CYP3A4 metabolism, does not show a substantial increase in serum concentrations due to grapefruit juice consumption.3 Nonetheless, pharmacists should warn patients to avoid drinking large volumes of grapefruit juice simultaneously with any calcium antagonist. Otherwise, patients may be at an increased risk of such side effects as orthostatic hypotension.

The phosphodiesterase inhibitors, sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), used for erectile dysfunction, can also increase blood levels with concurrent use of grapefruit juice, but this interaction is unpredictable. While the clinical effects of the interaction are less pronounced than other classes of drugs, patients may have a slightly higher risk of adverse reactions, such as priapism, hypotension, and visual disturbances.1,3

Estrogen-containing oral contraceptives are also affected by grapefruit juice; their serum levels increase only modestly when grapefruit juice is used concomitantly.3 Tricyclic antidepressants are affected by grapefruit juice because they are also substrates for CYP3A4; clomipramine (Anafranil) is considered to be the most well-documented drug of this class to interact. Diazepam (Valium), temazepam (Restoril), and midazolam (Versed) are interacting agents of the benzodiazepine class that have increased concentrations and central nervous system depressant effects with grapefruit juice.1,3  However, other benzodiazepines (e.g., lorazepam, oxazepam) do not appear to be affected. Grapefruit juice doubles the oral systemic effects of budesonide (Entocort), increasing the risk of the already prevalent glucocorticoid effects.3 Buspirone levels and carbamazepine levels are increased with concurrent administration of grapefruit juice.1 Although ziprasidone levels can be elevated by concurrent consumption of grapefruit juice, other atypical antipsychotics do not appear to be affected.3

It is important to note that coadministration of grapefruit juice with the antiarrhythmic drug amiodarone can be problematic. The AUC of amiodarone was increased by 50% in 11 subjects when given with grapefruit juice (three 300-mL glasses on the day of amiodarone administration).4 However, amiodarone has an active metabolite that is also inhibited by grapefruit juice, making the net clinical effect of the interaction difficult to predict.

Another potentially significant grapefruit juice interaction is with the immunosuppressant tacrolimus (Prograf). This drug is often used following organ transplantation. Due to the ability of grapefruit juice to inhibit the metabolism of tacrolimus, the manufacturer recommends avoiding the use of grapefruit juice during therapy.

Caffeine
Not only do foods affect the metabolism of drugs, but also in some cases, drugs interact with and alter the metabolism of food additives, such as caffeine. While it is appropriate to consider caffeine as a drug itself, rather than a food additive, some patients may disregard the fact that a high content of caffeine is found in coffee, tea, soft drinks, and other "energy" foods and beverages. Many common drugs interfere with the metabolism of caffeine, resulting in an increase in caffeine blood levels. Consumption of caffeinated beverages late at night in combination with these medications may result in sleepless nights. In addition, this may enhance caffeine's diuretic effect. Ciprofloxacin inhibits the metabolism of caffeine, resulting in increased effects of caffeine.3 The other fluoroquinolones do not appear to affect the metabolism of caffeine and may therefore be seen as alternatives for patients who consume large amounts of caffeine during the day. Cimetidine also increases caffeine levels, thus a different H2 antagonist (e.g., ranitidine, famotidine) should be administered in caffeine users. Oral contraceptives and prednisone also increase caffeine levels due to the inhibition of caffeine metabolism.3 Conversely, caffeine inhibits the metabolism of theophylline, which shares a similar chemical structure with caffeine, and can increase the serum concentrations of theophylline.1 Pharmacists should warn patients taking theophylline that caffeine-containing beverages may predispose patients to adverse theophylline-related effects, such as jitteriness, insomnia, and cardiac arrhythmia.

Dairy Products/Calcium

In contrast to caffeine and grapefruit juice, the use of dairy products containing calcium may cause a chemical interaction, not a metabolic interaction. The calcium ion chelates with the drug and may decrease its absorption. Most pharmacists are familiar with the typical antacid and dairy product interactions. However, an increasing number of foods is being fortified with calcium. Orange juice, bread, and other foods enriched with calcium can result in the same type of interactions seen with calcium-containing antacids and dairy products.5 The fluoroquinolones (e.g., ciprofloxacin, levofloxacin) may be rendered ineffective when taken at the same time as dairy products or calcium supplementation.2,5 Most manufacturers suggest minimizing this interaction by administering an oral quinolone at least two hours before or six hours after the dose of an oral calcium supplement or calcium-rich food. Patients should be monitored for decreased therapeutic effects of oral quinolones if administered with oral calcium supplements. Tetracyclines also interact with concurrent administration of calcium and/or dairy products high in calcium. Bisphosphonates (alendronate, risedronate, and ibandronate) have low bioavailability, and little drug is absorbed when given with any type of food or beverage other than water; this is especially problematic with dairy products.

Levels of cefuroxime, a cephalosporin antibiotic, are decreased when taken with dairy products.1 Other cephalosporins do not appear to be affected. In addition, methotrexate levels are decreased with the consumption of milk-rich foods.3 As a general rule, administration of dairy products and/or calcium supplements should be separated from the interacting drug by at least two to four hours.

Protein-Rich Foods

Protein-rich foods can interfere with or potentiate the absorption of various medications. Consuming a meal high in protein and taking propranolol  concurrently can increase the beta-blocker's bioavailability. When propanolol was given with protein-rich foods, a mean increase in bioavailability of 53% was reported.6 Coadministration of protein and propranolol may increase such adverse events as bradycardia, hypotension, and, due to nonselectivity for beta-1 receptors, bronchoconstriction.3 High-protein diets can decrease concentration and efficacy of carbidopa/levodopa and theophylline, resulting in subtherapeutic conditions and exacerbation of conditions.1

High-Fat Meals

Many drugs have their pharmacokinetics altered by fatty foods. Most drug monographs will list that maximum concentration is decreased, but total absorption remains the same. 3 Due to the multitude of these medications and the variability observed, they are not discussed in this article. Some drugs have altered pharmacokinetics based on the fatty content of meals. For example, griseofulvin has a significantly increased absorption when taken with food, especially a high-fat meal. Thus, griseofulvin is recommended to be taken with a fatty meal to benefit from this interaction.7 However, this should be done on a consistent basis, and certain extended-release formulations may show increased "dose-­ dumping" with fatty meals, whereas others do not.8

Fiber

Fiber, much like calcium, works to bind drugs, resulting in decreased concentrations. For example, patients with diabetes who try to decrease their cholesterol levels by eating oatmeal after taking metformin might be worsening their diabetic control. Metformin blood levels are decreased when taken with large amounts of fiber.1 Levothyroxine is another drug that is altered when taken with fiber. Digoxin and penicillin are also affected by this food–drug interaction. However, other antibiotics in the penicillin class do not appear to be altered by the use of dietary fiber.1,3

Vitamin C and Fruit Juices

Increasingly more fruit juices are fortified with vitamin C and other vitamins, if they do not contain them already. The absorption of amphet­ amine-containing drugs (e.g., Adderall) is altered, increased, or decreased if taken with acidic food or juices or vitamin C.3 Maximal absorption of amphetamines occurs in the intestinal alkaline environment. Acidic fruits or juices consumed concurrently with these drugs may impair gastrointestinal absorption. Foods that acidify the urine may increase renal clearance of amphetamines, leading to lower drug levels. In addition, fexofenadine levels are decreased when taken with fruit juices. Other second-generation antihistamines, such as cetirizine and loratadine, may be affected but not to the same extent as fexofenadine.1,2 One of the largest populations that take these medications--children (for attention-deficit hyperactivity disorder)--should avoid taking these drugs with apple or orange juice in the morning.

Tyramine-Containing Foods
Tyramine is a chemical found in foods and beverages such as cheese and red wine. It has a significant interaction with monoamine oxidase inhibitors (MAOIs). These drugs are used infrequently but are occasionally used to treat depression and are becoming increasingly popular for the treatment of Parkinson's disease. Linezolid, a newer oxazolidinone antibiotic, has some MAOI properties, thus showing characteristics and potential for this interaction.1 Therefore, linezolid should be used cautiously in patients taking serotonin selective reuptake inhibitors (SSRIs).3 Lastly, isoniazid, a mainstay in the treatment of tuberculosis, also exhibits MAOI effects and should not be taken with tyramine-containing foods.1,9

Warfarin
Consistency is the key with warfarin in all circumstances. The most notorious food–drug interaction regarding warfarin occurs with "green, leafy vegetables" due to their rich vitamin K content. Warfarin, by its mechanism of action, interferes with the synthesis of vitamin K–derived clotting factors.3 Increasing vitamin K intake will result in more clotting factors, reducing the efficacy of warfarin. Some people erroneously believe that warfarin recipients cannot eat any green, leafy vegetables. However, if patients remain consistent with vitamin K intake, taking their medication as directed, the interaction is not substantial. Yet, when patients become vegetarians or avoid these foods completely after regular consumption, adverse events or changes in INR (international normalized ratio) occur. Soy milk, char grilled foods, and sushi containing seaweed may also decrease the effect of warfarin.10 Cranberry juice, in contrast, can significantly increase INR and potentiate the anticoagulant effects of warfarin.2

Alcohol

While not a food per se, drug interactions with alcohol are numerous and important. The list of drugs that have sedating properties when used with alcohol is nearly endless. Some examples are benzodiazepines, antidepressants, barbiturates, antihistamines, opiates, muscle relaxants, antipsychotics, and anticonvulsants. When these drugs are taken concurrently with alcohol, patients are at an increased risk of ataxia, somnolence, respiratory depression, and motor impairment, which can lead to falls, accidents, and injury. Excessive use of acetaminophen with regular alcohol intake increases the risk of hepatotoxicity. Patients should be advised not to exceed 4 g of acetaminophen in 24 hours and consult their physician if they regularly drink three or more alcoholic drinks per day. A disulfiram reaction (facial flushing, vomiting, tachycardia) can occur if alcohol is ingested with drugs such as metronidazole, sulfonylureas, or isoniazid.

Other Significant Interactions
Levothyroxine should not be taken with foods that may be goitrogenic.3 High sodium intake can decrease drug levels of lithium, and low sodium intake can increase levels of lithium; thus, consistency and moderation is important. 1 In addition, patients with hypertension and those with heart failure should avoid sodium as much as possible, since it can exacerbate symptoms of both conditions.1 Colchicine and metformin decrease the absorption of vitamin B12, which may have an impact in patients with certain types of anemia. Phenobarbital and corticosteroids decrease calcium absorption. As a result, patients on long-term corticosteroid treatment should have high levels of calcium supplementation, as well as a bisphosphonate for osteoporosis prevention.1,3 Lastly, patients taking an angiotensin-converting enzyme inhibitor or potassium-sparing diuretic (e.g., spironolactone or triamterene) should avoid excessive potassium intake, as these drugs already increase potassium levels in the body.3

Conclusion
As evidenced by all of the interactions discussed, it appears that the safest thing to take medications with, unless clearly known otherwise, is a large glass of water. Fad diets may bring new interactions that are unknown. For example, pomegranate juice is becoming increasingly popular and has shown implications of inhibiting CYP3A4, similar to grapefruit juice. Thus far, no drug interactions have been directly linked to it, but the juice should be considered as a potential offender.11 Whenever possible, pharmacists should discuss drug administration instructions with each patient. In cases where certain foods or beverages are known to impact therapy, the pharmacist should determine the clinical relevance, if any, and advise patients appropriately. Many drugs also interact with alcohol, herbal therapy, and dietary supplements. Thus, it is important for the pharmacist to take a thorough dietary history to determine if patients need additional counsel about medication administration.

References

1. Leibovich ER, Deamer RL, Sanserson LA. Food-drug interactions: careful drug selection and patient counseling can reduce the risk in older patients. Geriatrics. 2004;59:19-33.

2. Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol. 2004;44:559-569.

3. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Drugs – Comprehensive and specialty fields. Hudson, OH: Lexi-Comp, Inc; 2006.

4. Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol. 2000;49:373-378.

5. Wallace AW, Amsden GW. Is it really ok to take this with food? Old interactions with a new twist. J Clin Pharmacol. 2202;42:437-443.

6. Liedholm H, Wahlin-Boll E, Melander A. Mechanisms and variations in the food effect on propranolol bioavailability. Eur J Clin Pharmacol. 1990;38:469-475.

7. Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001.

8. Wonnemann M, Schug B, Schmucker K, Brendel E, et al. Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union. Int J Clin Pharmacol Ther. 2006;44:38-48.

9. Kaneko T, Ishigatsubo Y. Isoniazid and food interactions: fish, cheese, and wine. Intern Med. 2005;44:1120-1121.

10. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106.

11. Summers KM. Potential drug-food interactions with pomegranate juice. Ann Pharmacotherapy. 2006;40:1472-1473.

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