A food-drug interaction is the result of a physical, physiological or chemical relationship that occurs between a drug and a product consumed as a food/nutrient.1
When they occur simultaneously, food and drug intake can have an effect on the pharmacological, pharmacokinetic, and pharmacodynamic properties of the drug. Consequently, food-drug interactions affect the effectiveness and safety of pharmacotherapy. As a result, the Food and Drug Administration (FDA) has published multiple guidelines encouraging the pharmaceutical industry to investigate food-drug interactions during drug development.2
Food-drug interactions can affect pharmacotherapy in many ways; therefore, knowledge about these interactions and advice are important for clinicians.
Few studies have reported on the prevalence of food-drug interactions. In adults, the prevalence of these interactions ranged from 6.3% in intensive care unit (ICU) patients with enteral nutrition3 to 58.5% in elderly patients cared for by a public primary care service.3 Currently there are no studies that report the prevalence of food-drug interactions in pediatrics.
The objectives of this review were to identify the most common food-drug interactions observed in pediatrics and discuss how to advise patients and their families to avoid these interactions.
| Effects of food-drug interactions |
Food-drug interactions can lead to increased adverse effects (positive effect) or decreased effectiveness (negative effect). A positive effect occurs when food consumption increases the bioavailability of drugs. The main cause of the positive effects of food is the increased dissolution and solubilization of drugs that are poorly soluble in water in the fed state.
Gastrointestinal (GI) fluid contains solubilizing agents such as bile salts that improve solubilization capacity, leading to increased positive effects. Formulation strategies such as nano-sized preparations, amorphous and solid dispersions, and lipid-based formulations are used to help mitigate positive effects.2 For example, nanosized preparations ensure action at the target site because a Smaller particle offers easier drug absorption at the cellular level, allowing for more effective drug delivery.4
On the contrary, a negative effect decreases the bioavailability of the drug. Food can delay the disintegration of immediate-release products or bind to the drug, leading to negative effects. The contents of the upper gastrointestinal tract are viscous, which causes inhibition of the disintegration of the formulation. As a result, drug release is prevented and drug diffusion to the absorptive membranes of the GI tract is hindered.
Formulation strategies such as delayed-release, enteric-coated, and modified-release formulations are used to help mitigate negative effects. For example, enteric-coated formulations help the drug be released lower in the GI tract, allowing for greater absorption.2
Although useful, these strategies are not perfect because they may be subject to food effects, such as delayed gastric emptying with the potential for exaggerated drug effect, or "dose dumping." The larger the formulation size, the longer the gastric emptying period in the fed state and the greater the variability. Meal timing subsequently affects the efficacy of modified-release formulations because the presence of food in the stomach can stimulate increased gastric motility and accelerate small intestinal transit, thereby reducing drug absorption time.2
| Types of food-drug interactions |
Interactions between foods and drugs can be pharmacological, pharmacokinetic and pharmacodynamic.5
> Drug interactions
Drug interactions occur with delivery devices or enteral feeding products. For example, phenytoin may bind to the protein components of the enteral feeding product, decreasing its effectiveness. It should be noted that this interaction exists with enteral feeding products, nutritional supplements and foods.
Another important consideration for patients with feeding tubes is drug interactions between the delivery device (the feeding tube itself) and the medications.
Ciprofloxacin oral solution is oil-based and may stick to feeding tubes, reducing their absorption.5 In such cases, certain modifications may be made, such as prescribing ciprofloxacin tablets with instructions for crushing them or switching to another antibiotic such as levofloxacin for avoid drug interactions.
> Pharmacokinetic interactions
Pharmacokinetic interactions occur when foods affect the movement of drugs through the body through processes such as drug absorption, distribution, metabolism, and elimination.5
Absorption is the movement of a drug from the site of administration into the bloodstream. Divalent cations in dairy products can chelate doxycycline, decreasing its absorption.
Distribution is the movement of a drug through the vascular system to various body tissues (fat, muscle, and brain tissue) and the relative proportions of drug in those tissues.5 It may be affected primarily by binding to plasma proteins via lipoproteins. , albumin and α1-acid glycoprotein. Food can bind to the same site as cyclosporine, displacing it and causing its volume of distribution and bioavailability to be altered.6
Metabolism is the biotransformation of pharmaceutical substances in the body to allow better elimination. One of the main metabolic mechanisms is through cytochrome P450 (CYP) enzymes.
CYP enzymes are found in cells throughout the body; However, the majority of CYP enzymes involved in drug metabolism are found in the liver and intestine. These CYP enzymes represent 70% to 80% of the enzymes involved in drug metabolism. There are approximately 60 CYP genes in humans that are involved in the formation (synthesis) and breakdown (metabolism) of various molecules and chemicals in cells.5
CYP3A and CYP2C9 are the main CYP enzymes and account for more than 95% of the CYP content. CYP metabolism in the small intestine causes first-pass metabolism of many drugs, most commonly tacrolimus, midazolam, nifedipine, and simvastatin.2 CYP enzymes can be induced or inhibited by foods or medications. CYP inducers increase the metabolism of the drug, reducing its effectiveness.
CYP inhibitors decrease drug metabolism, increasing adverse effects. For example, grapefruit juice inhibits the CYP3A4 metabolism of simvastatin, thereby increasing its adverse effects.5
Elimination is the process by which a drug is excreted from the body, either in unchanged form or modified as a metabolite. Lithium and sodium may compete for tubular reabsorption in the kidney, leading to impaired lithium elimination. For example, a sudden decrease in potato chip consumption may result in a higher serum lithium level, leading to increased toxicity due to decreased renal clearance.5
With pharmacokinetic interactions, clinicians should keep in mind that the timing of food consumption, whether a few hours before or a few hours after administering the drug, may prevent alterations in the absorption, distribution, metabolism, or elimination of the drug. Foods that are commonly prone to drug interactions include grapefruit juice, leafy greens, and dairy products, which are discussed later in terms of management.
> Pharmacodynamic interactions
Pharmacodynamic interactions occur when foods alter a clinical effect of the drug on the body.
Some foods can enhance the effects and toxicity of the drug, leading to adverse reactions. For example, warfarin is a competitive inhibitor of vitamin K epoxide reductase complex 1 (VKORC1), which is an essential enzyme that activates vitamin K in the body.
When warfarin is administered with vitamin K-rich foods such as kale and spinach, warfarin depletes vitamin K stores by competitively inhibiting VKORC1. As a result, warfarin reduces the synthesis of coagulation factors II, VII, IX, and X, as well as the coagulation regulatory factors protein C and protein S.
A diet rich in vitamin K antagonizes the therapeutic effect of warfarin, increasing the risk of clots.5 In these cases, dietary modifications, such as maintaining constant amounts of vitamin K, can prevent pharmacodynamic interactions.
| Clinical aspects (symptoms, signs, laboratory tests and diagnosis) |
Food-drug interactions should be suspected when a patient is taking their medications as directed and the doses are correct but the therapy is not yet optimal (increased adverse effects, decreased effectiveness, new adverse effects, etc.).
In all individuals with suspected food-drug interactions, it is recommended to evaluate the patient’s dietary history, baseline laboratory values, drug concentrations, and prescription history.
> Food history
To discover interactions between foods and drugs, the interview with the patient/caregiver is key. It is important to know what the patient is eating and the timing of administration of both meals and medications. Important details include feeding method (oral, feeding tube, or total parenteral administration), feeding frequency (intermittent or continuous), and diet composition (whole food or enteral nutrition formula).
The doctor should be sure to ask if the patient eats/drinks high-risk foods involved in certain food-drug interactions, such as whole/juiced citrus fruits, leafy green vegetables, dairy products, or foods containing tyramine (e.g., aged cheeses). , cured meats, pickled foods).
Although pediatric patients should not consume alcohol because it is against the law in the United States, they should be asked about their consumption to detect possible interactions. Other pertinent information to collect includes whether the patient has a consistent diet or takes vitamins/minerals.
> Reference laboratory values
If applicable, baseline laboratory values are useful in evaluating food-drug interactions. The clinician should use the drug in question to help guide which laboratory tests to choose.
The adverse effects and metabolism associated with the drug in use can guide physicians as to which laboratory tests to order.
As previously mentioned, many factors, such as CYP enzymes, kidney dysfunction, and liver dysfunction, play a role in metabolism; therefore, obtaining baseline renal or hepatic function may be useful.
Laboratory values may reveal food-drug interactions if they are altered from baseline levels.
> Drug concentrations
To measure the efficacy or toxicity of a drug, it is recommended to know its concentrations, if applicable. A consultation can be made to the pharmacy team if there is uncertainty regarding the need for a medication level, the type of level (maximum, minimum or random), and the measurement time regarding its administration.
Factors to consider include the usefulness of the drug concentration, price, laboratory capacity (whether the level can be obtained in-house or requires sending to an outside laboratory), and timing of results. Drug concentrations may be most useful when evaluating food-drug interactions with tacrolimus, sirolimus, phenytoin, carbamazepine, cyclosporine, and barbiturates.
> Prescription history
Prescription history is a useful tool for evaluating when food-drug interactions may have occurred. Important details to note include when the medication was first prescribed and when doses were increased/decreased. It is also important to consider dispensed formulations because formulation modifications can help mitigate some interaction issues. For example, an oral solution with a lower alcohol content or a crushed tablet may be prescribed for a patient taking metronidazole to avoid a reaction to disulfiram.
| Driving |
> Fruit juices
Fruit juices are known to cause many drug interactions.
It should be noted that the interactions discussed with juices also apply to whole fruits. Grapefruit, orange, tangerine, grapes, mango, apple and papaya have known drug interactions with statins and diazepam. Food-drug interactions are more commonly seen with grapefruit juice over other juices.
Other fruit juices may interact with medications; However, patients generally do not consume enough to cause an interaction.5 More than 85 medications interact with grapefruit juice because it inhibits CYP3A4, CYP1A2, and P-glycoprotein. Grapefruit juice interacts with different medications in many ways. increase/decrease metabolism.
One of the most common food-drug interactions occurs when grapefruit juice is administered concomitantly with statins. Grapefruit juice increases the toxicity of statins, causing muscle pain, elevation of creatine phosphokinase level, or, in some cases, rhabdomyolysis. When taking statins, patients/caregivers should be advised to avoid simultaneously ingesting large amounts of grapefruit juice (> 1.2 L per day) before starting therapy.7
The absorption of levothyroxine is also decreased when taken with grapefruit juice, so it should be administered first thing in the morning on an empty stomach at least 30 minutes before eating.
Alternatively, levothyroxine can be administered consistently at night, 3 to 4 hours after the last meal. Grapefruit juice may increase the area under the curve of many drugs, including amiodarone, carbamazepine, cyclosporine, and oxycodone. As a result, grapefruit juice increases total body exposure over time to these drugs. Additionally, grapefruit juice may increase blood levels of tacrolimus and sirolimus, increasing nephrotoxicity.
Other fruits, such as oranges, lemons, and strawberries, can help increase the absorption of medications that require a more acidic environment. For example, fruits containing ascorbic acid may increase iron absorption by creating a more acidic GI environment to help iron dissolve properly for absorption.5 Additionally, fruit-drug interactions may be affected by the genetics of the patient. For example, apple juice reduces fexofenadine more significantly in patients with the SLC2B1 c.1457C>T.8 allele.
In cases of lack of response to medications, pharmacogenomics may be useful. Cost, insurance coverage, availability of pharmacogenomic panels, and turnaround time are important factors to consider when exploring pharmacogenomics as a cause of adverse food-drug interactions.
In general, when counseling patients about fruit-drug interactions, it is important to keep in mind that most interactions depend on the amount of juice or whole fruit consumed. If fruit-drug interactions exist, the patient should be consistent with their fruit juice consumption or eliminate it completely.
Specifically for grapefruit juice, separating the timing of consumption from medication intake does not necessarily prevent drug interactions. Grapefruit juice and whole fruit may need to be avoided completely.6,7,8 Patients and caregivers should be advised to read product labels carefully, especially with fruit juice mixtures because some may contain grapefruit.5
If clinically applicable, a pharmacogenomics panel can assist in guiding treatment.
> Dairy
Dairy products contain divalent metal ions such as iron, calcium and magnesium. When administered with certain medications, cations form complexes with drugs that become insoluble precipitates or soluble complexes that are not absorbed.9 Dairy products also chelate medications, resulting in decreased drug absorption.
As a result, tetracycline and fluoroquinolone antibiotics should be taken 2 hours before or after dairy products such as yogurt, cheese, and milk to avoid chelation.
For example, the bioavailability of ciprofloxacin can be reduced by 27% to 67% when combined with dairy products.5
In addition, dairy products decrease the absorption of bisphosphonates such as alendronate, zoledronate, risedronate or pamidronate.5 Bisphosphonates should be taken immediately upon waking in the morning on an empty stomach; They should never be taken with dairy products and meals should be given at least 1 hour after bisphosphonate administration. Levothyroxine absorption is also reduced by divalent cations present in dairy products. Levothyroxine should be taken in the morning on an empty stomach at least 30 minutes before meals or in the evening 3 to 4 hours after the last meal.5
When counseling patients/caregivers about interactions between dairy products and medications, it is important to tell them to read product labels because many products, including those used for enteral nutrition, may contain dairy products. Dairy-free products can help eliminate drug interactions; however, the suitability of these products may depend on the age of the patient. Clinicians should collaborate with pharmacists and nutritionists to determine the timing of medication administration separately from dairy product consumption to avoid dairy-drug interactions.
> Vitamin K
Phytonadione, also known as vitamin K1, inhibits CYP1A1 and CYP3A4. The highest content of vitamin K is present in green leafy vegetables, such as broccoli, cabbage, Brussels sprouts and spinach. Vitamin K is necessary for the synthesis of coagulation factors (factors II, VII, IX and X and proteins C, S and Z) and is a pharmacological antagonist of warfarin. As discussed earlier in this paper, warfarin is a competitive inhibitor of VKORC1, which activates vitamin K in the body. Occult sources of vitamin K may decrease or reverse the activity of warfarin, lowering international normalized ratio (INR) levels and rendering warfarin subtherapeutic.5
To avoid interactions between vitamin K and medications, it is vital to counsel the patient. Consistency is key with warfarin and vitamin K. Vitamin K is present in foods such as miso, cranberries, carrot juice, tuna, sauces, prunes, and tomatoes, all of which are not green or leafy, so Patients/caregivers may not be aware.
Before starting warfarin treatment, it is advantageous to ask the patient to keep a food diary to estimate the total amount of vitamin K normally consumed.
With that as a guide, the patient can maintain a controlled intake of vitamin K. Fruit juices may contain mixtures that provide vitamin K; therefore, patients should read product labels to ensure controlled consumption. Additionally, patients taking warfarin should avoid multivitamins, natural products, and dietary supplements that have added vitamin K. Patients should always consult doctors/pharmacists before starting to consume these products.9
> Tyramine
Tyramine comes from the breakdown of proteins in food. It can be found in aged, fermented, or long-stored foods, such as aged cheese, meat, wine, beer, and chocolate. To avoid tyramine, patients should consume mostly fresh foods that are cooked and eaten on the same day. Leftovers should be discarded within 24 to 48 hours. Processed meats should be limited to 4 oz per day and tofu/tempeh should be limited to 10 oz per day.
Tyramine interacts with linezolid, isoniazid, and monoamine oxidase inhibitors such as isocarboxazid, rasagiline, seligiline, and phenelzine.
When taken together, the combination of these medications and tyramine may increase the patient’s risk of hypertensive crisis. Hypertensive crisis presents with symptoms such as severe headache, nosebleeds, severe anxiety, chest pain, blurred vision, and confusion.10 Patients should avoid foods containing tyramine while taking monoamine oxidase inhibitors. Linezolid can be taken with foods containing tyramine if the medication is administered 6 hours before or after eating foods containing tyramine.5
> Alcohol
Alcohol should not be a concern in pediatric patients, but this cannot be assumed due to the possibility of underage drinking. Pediatric patients should also be advised to avoid alcohol consumption as it is not only against the law in the United States, but could also negatively affect drug interactions and health. Additionally, it is important to consider the alcohol content in certain oral solutions/elixirs to avoid drug interactions. Medications such as phenobarbital, digoxin, diazepam, and dronabinol contain more than 10% alcohol by volume.11,12,13
Some alcohol-drug interactions may cause increased adverse effects and/or sedation.
The most common alcohol-drug interaction occurs with metronidazole and is known as the disulfiram reaction, which presents with headache, nausea/vomiting, chest pain, dizziness, thirst, and weakness. Barbiturates and diazepam may increase cognitive impairment and sedation when taken with alcohol. When alcohol is taken with hepatotoxic medications such as acetaminophen, ketoconazole, or rifamycin, additive hepatotoxicity may occur.6
It may be useful to check the alcohol content of medication when directing patients to oral solutions or elixirs. Package inserts typically report the alcohol content. If that information is not in the package insert, your doctor can contact the manufacturer. It must be verified that there are no drug interactions between alcohol and the drug in question. When possible, oral formulations containing large amounts of alcohol should be avoided.11
> Food
Foods affect drug absorption by altering GI pH, delaying gastric emptying time, increasing splanchnic blood flow, and stimulating bile flow or physically interacting with drugs.
Proper timing of meals is vital to prevent interactions.14
Foods can increase or decrease bioavailability and may help reduce the gastrointestinal adverse effects of medications. Fexofenadine and isoniazid should be taken on an empty stomach to ensure adequate absorption.
The proton pump inhibitors zolpidem and captopril are best taken 30 to 60 minutes before food to increase effectiveness. Bisphosphonate and phenytoin concentrations decrease with food and should therefore be taken 30 minutes before the first meal of the day or 4 hours after the last meal of the day.
The absorption of levothyroxine is decreased by many food components, including soy flour, soybeans, espresso coffee, nuts, calcium, iron, and dietary fiber. Therefore, levothyroxine should be taken in the morning on an empty stomach at least 30 minutes before a meal or in the evening 3 to 4 hours after the last meal.
Ferros o sulfate works better on an empty stomach; However, it can be given with foods in general to reduce gastrointestinal discomfort and specifically with foods containing vitamin C to increase absorption. Drugs such as cannabidiol and ziprasidone are better absorbed when administered with high-fat foods because these foods provide a lipophilic environment that improves their solubilization.5
To prevent orthostatic hypotension , carvedilol should be administered with food. Nitrofurantoin, nonsteroidal anti-inflammatory drugs, corticosteroids, potassium chloride, and metformin are best administered with food to prevent gastrointestinal upset. Tamsulosin should be taken 30 minutes after meals to ensure that it is not absorbed too quickly because food can increase its absorption.
Cyclosporine oral solutions and capsules should be administered on a consistent schedule relative to meals and time of day to avoid fluctuating drug concentrations. Food can increase carbamazepine levels and subsequently cause further toxicity. Carbamazepine levels and toxicity should be monitored with instructions to maintain a consistent diet.5
Knowing the optimal time to administer a medication in relation to diet is vital to achieve drug effectiveness without unwanted adverse events such as toxicity. When discharged from an inpatient setting or outpatient setting, patients/caregivers should be counseled on appropriate medication timing in relation to feeding. Precise instructions should also be written in the prescription and discharge summaries.
> Enteral nutrition
Enteral nutrition can cause both pharmacokinetic and pharmacodynamic interactions.
Patients receiving continuous enteral nutrition need careful consideration when initiating medications such as tetracyclines, antihistamines, fluoroquinolones, phenytoin, levothyroxine, and carbamazepine. For medications such as tetracyclines and antihistamines, which are best taken on an empty stomach, it is recommended that enteral nutrition be discontinued for 1 hour before or 2 hours after drug administration to prevent decreased absorption.
Phenytoin binds to protein components of enteral nutrition and its concentrations are markedly reduced, resulting in increased seizure frequency.
Recommendations for this food-drug interaction include discontinuing enteral nutrition 2 hours before and after phenytoin administration. Some doctors have also modified the phenytoin dosing schedule to twice daily. With this method, enteral nutrition is withheld for 1 hour before and after the dose, allowing only 4 hours of interrupted nutrition per day.
Levothyroxine bioavailability and serum thyroid hormone levels may be reduced when levothyroxine is administered during enteral nutrition. Patients should be monitored for signs and symptoms of hypothyroidism. Doctors should consider increasing the dose if this medication is taken with food via an enteral tube. Levothyroxine should not be administered within 4 hours of ingesting products containing calcium or iron.15
Enteral nutrition products have the potential to cause interactions with warfarin and vitamin K because the vitamin K content in these products ranges from 0 to 125 µg/1,000 kcal. To maintain adequate anticoagulation, enteral nutrition products and tube feeding rates should be closely monitored. Any variation in the prescription of enteral nutrition support may justify changes in warfarin doses.16
According to the American Society for Enteral and Parenteral Nutrition guidelines, a washout protocol should be used to avoid formula-drug interactions and to prevent blockages.17 Strategies such as compressing tube feeding and nighttime administration may also help reduce the potential for formula-drug interactions. When tube feeding is discontinued, it is imperative to do so for a short period of time to ensure that the patient’s nutritional status is not affected.16,18
| Follow-up |
At each visit, it is important for all members of the healthcare team to ask about the patient’s current diet and medications. If applicable, therapeutic drug monitoring should be used to monitor efficacy or toxicity. The clinical results of medications should be monitored without standardized assays to measure their plasma concentrations.16
Physicians can collaborate with pharmacists to appropriately schedule medication administration and prevent food interactions. Patient counseling and collaboration among health care teams (nurses, doctors, pharmacists, and dieticians) can help avoid food-drug interactions. As a result, therapy can be optimized by avoiding adverse effects.
There are many resources on special diets in online databases such as Lexicomp and Micromedex. These resources can be a great tool to give families during counseling. Other tools such as printed medication administration calendars or smartphone apps can also help families remember administration times and avoid food-drug interactions.
Together, healthcare teams can ensure appropriate patient and family education about the types of food-drug interactions, timing of food and drug administration, and avoidance of certain foods (if necessary), by striving for patient safety and preventing adverse events.
| Comment |
The food-drug interaction results from a physical, physiological or chemical relationship that occurs between a drug and a product consumed as food or nutrient. This interaction can affect pharmacotherapy in many ways; therefore, knowledge about these interactions and advice are extremely important.
Taking a detailed medical history about the patient’s history, current medications and general diet, knowing the possible food-drug interactions and providing detailed and timely information about the form and timing of medication administration in relation to meals will allow greater therapeutic efficacy while The probability of adverse effects related to these interactions is reduced.
