Medication Interactions with Food

Patients are often given advice on when to take their medication in regards to food. For example, some medicines may be better absorbed on an empty stomach, while others may be better tolerated when taken with food. Not as much attention is typically given to the types of food taken with medicine. However, specific components of foods can affect the pharmacokinetics and pharmacodynamics of many medications in a number of different ways.

Chelation

Some medicines can bind to divalent and trivalent cations to form insoluble complexes that cannot be absorbed. Cations are positively charged ions that include calcium, aluminium, iron, magnesium, and zinc. These cations may be found in foods, such as dairy products, as well as supplements and antacids.

Medications typically associated with food interactions due to chelation include:

• Quinolone antibiotics, e.g. ciprofloxacin, moxifloxacin, and norfloxacin;
  • Dairy products should not be taken within two hours of oral ciprofloxacin or norfloxacin dose.
  • High dose calcium supplements have demonstrated only minor impacts on the rate of absorption of moxifloxacin which is not considered clinically relevant. Therefore, dairy products may be consumed with moxifloxacin.
• Tetracycline antibiotics, e.g. doxycycline, minocycline, and tetracycline;
  • Tetracycline (not marketed in Australia) is most likely to be affected by this interaction and should not be taken within two hours of dairy products.
  • Doxycycline and minocycline are much less likely to be affected by the ingestion of dairy products. Although they should not be co-administered with calcium supplements, these medicines can be safely taken with dairy products.
• Bisphosphonates, e.g. alendronate, ibandronic acid, and risedronate;
  • These medicines are poorly absorbed, and administration with food or products containing calcium, magnesium and aluminium further reduces their bioavailability.
  • Regular immediate-release formulations of these medicines must be taken on an empty stomach and swallowed with only plain water.
  • Some bisphosphonate products are enteric-coated and formulated with the chelating agent, EDTA (disodium edetate). EDTA is poorly absorbed but exhibits a local effect in the gastrointestinal tract by preferentially binding calcium and other cations present in food. These preparations (e.g. Actonel® EC) are not markedly affected by food.
• Chelating agents, e.g. penicillamine, trientine
  • The chelating properties of these agents are used to advantage in order to remove substances from the body, e.g. to reduce copper levels in people with Wilson’s disease.
  • If these medicines bind to cations in the contents of the gastrointestinal tract, their absorption and efficacy will be significantly reduced. These medicines should, therefore, be given on an empty stomach and at least one hour apart from food and milk.

Grapefruit juices

A component of grapefruit can irreversibly inhibit the intestinal CYP3A4 enzyme. This may increase the bioavailability of medicines metabolised via this pathway, leading to increased therapeutic effect and an increased risk of adverse effects. For pro-drugs metabolised via this pathway, such as clopidogrel and cyclophosphamide, co-administration with grapefruit juice may reduce efficacy due to reduced conversion to the active metabolite. A similar interaction may also occur with Seville oranges, starfruit, and pomelos.

Over 90 medicines are known to interact with grapefruit juice, although not all interactions are likely to be clinically relevant. The relevance is probably highest for medicines with low innate bioavailability (e.g. felodipine) and those with a narrow therapeutic index. For drugs with low bioavailability, a larger relative increase in systemic concentration is likely to occur, which may be more significant.

A selection of medicines that interact with grapefruit juice is shown below:

The enzyme inhibition caused by grapefruit juice is irreversible, and its effects can last for several days. Therefore, simply separating the medicine from ingestion of the juice will not avoid this interaction. In addition, the effect of grapefruit juice on drug metabolism is highly variable between individuals. It is usually recommended that people avoid ingesting grapefruit juice while receiving the above medications.

Other fruit juices

Many other fruits contain substances that can interact with medicines. Grapefruit, apple, and orange juices contain components that may inhibit intestinal drug transporters, including P-glycoprotein and organic anion transporter polypeptides (OATPs). P-glycoprotein is an efflux transporter, inhibition of which may result in increased bioavailability. On the other hand, OATP is an influx transporter, and its inhibition may reduce the bioavailability of some medicines.

P-glycoprotein transports a wide range of medicines, including calcium channel blockers, ciclosporin, digoxin, macrolide antibiotics, and protease inhibitors. Medicines that use OATP for absorption include statins, angiotensin receptor blockers, beta-blockers, and fexofenadine.

One study demonstrated that grapefruit, orange and apple juice all caused a considerable reduction in fexofenadine absorption (between 30% and 40%). However, there are considerable interindividual differences in the activity of these drug transporters. This makes it difficult to predict clinically important interactions with these fruit juices. To further complicate the issue, there is a lot of overlap between substrates, inhibitors and inducers of P-glycoprotein, OATP and CYP3A4.

In comparison to the effect of grapefruit juice on CYP3A4, juices have a relatively transient impact on OATP. Separating the affected medicine from fruit juice by four hours should avoid this interaction.

This is an emerging area of research, and current evidence is limited.

Vitamin K

The therapeutic efficacy of warfarin can be affected by dietary intake of vitamin K. Vitamin K is required for the production of clotting factors, such as prothrombin. Therefore, increased intake of vitamin K can antagonise the effect of warfarin.

Vitamin K can be found in two main forms: phylloquinone and menaquinone. Phylloquinone (vitamin K1) is mostly found in green leafy vegetables such as kale, spinach, and broccoli. Menaquinone (vitamin K2) can be found in some animal-based and fermented foods such as liver, cheeses, kimchi, and kefir.

There is not a specific “warfarin diet”. People taking warfarin should eat a normal balanced diet and maintain a consistent amount of vitamin K. However, patients should consult with their doctor prior to making major dietary changes as more frequent blood tests may be required.

Protein

Some amino acids produced during protein digestion compete with levodopa for transport across the intestinal mucosa and into the brain. Diets high in protein may reduce the efficacy of levodopa therapy.

This interaction may not be clinically relevant for patients with early or moderate disease. However, this interaction may take on more significance for patients with advanced Parkinson’s disease. These patients are typically more sensitive to small changes in serum levodopa levels.

This interaction may be minimised by dosing levodopa on an empty stomach (30 minutes before meals or one hour after meals). However, some patients may tolerate levodopa better when taken with food. Other dietary modifications (e.g. protein limitation or redistribution diets) may be considered. This may be undertaken in conjunction with a dietician as people with Parkinson’s disease are at a greater risk of protein malnutrition which is associated with reduced quality of life in Parkinson’s disease.

Tyramine

Tyramine is a dietary amine that acts as an indirect sympathomimetic. It is normally metabolised by the monoamine oxidase (MAO) enzyme. However, in the presence of MAO inhibitors, excess levels of tyramine can occur and lead to a sympathomimetic toxidrome.

Tyramine reactions typically occur within 90 minutes of ingestion of tyramine. Severe headache and increased blood pressure can result.

Tyramine-rich foods include aged cheese, yeast extracts, pickled herrings, and cured or smoked meats. These foods should be avoided in patients taking irreversible MAO inhibitors (e.g. phenelzine, tranylcypromine) and for two weeks after stopping therapy. This reaction is much less likely to occur with reversible MAO inhibitors (e.g. moclobemide, linezolid), particularly at recommended doses. However, dietary restrictions may be necessary with reversible MAO inhibitors, particularly when higher doses or multiple agents are used.

Caffeine

Caffeine is metabolised by cytochrome P450 1A2 and may interact with medicines that also rely on this pathway. Potential interactions include:

• Increased clozapine levels – clozapine is a substrate for CYP1A2. Small studies suggest that caffeine intakes of 400-1000mg per day inhibit the metabolism of clozapine enough to be clinically significant for some patients. The Therapeutic Guidelines: Psychotropic recommend that clozapine blood levels be monitored weekly after caffeine intake changes; and
• Increased caffeine levels – inhibitors of CYP1A2 reduce the metabolism of caffeine and may lead to increased and prolonged caffeine effects. This could produce adverse effects such as tremor, palpitations, insomnia, and headache. Agents that may increase caffeine levels include fluvoxamine, ciprofloxacin, norfloxacin, and estrogens. Patients who consume high quantities of caffeine may need to lower their caffeine intake when initiating treatment with one of these medicines.

The toxic effects of caffeine are an extension of its pharmacological effects, and tolerance tends to develop. While caffeine is typically considered safe, accumulation can occur when its metabolism becomes saturated (due to a drug interaction or very high intake). This may overwhelm the usual mechanisms of tolerance and produce unpleasant effects in the individual.

Summary

Drug-food interactions are often variable and may be difficult to predict. Understanding the mechanisms behind these interactions can enable practitioners to identify and avoid clinically relevant drug-food interactions.