Always Read the Label: The Impact of Food-Drug Interactions

Most self-administered medication will come with instructions advising you on how and when to take the drug. Although swallowing a pill may not seem like it could be done incorrectly, instructions detailing the time of day to take a drug, and if the medication should be taken in with food or on an empty stomach, can have a significant impact on how effective and safe your medication is. The interactions between drugs and food are commonly known as the food-drug effect. A drug interaction is where a substance affects the activity of a drug, such as increasing or decreasing its effects. The most common drug interaction is between drugs taken concurrently by the same patient (drug-drug interaction), but food-drug interactions can also have a serious impact. The food-drug effect is a clinically recognised phenomenon where, in the case of some drugs, taking food at the same time can affect the body's ability to utilise the drug, or can cause additional side effects. 

The food-drug effect for each medication must be investigated independently, as different drugs can react differently in our bodies. Understanding the interaction between food and drugs is important to help predict how a drug will behave in the body and the extent to which the presence of food will change that behaviour. Thorough examination of food-drug interactions can prompt changes to drug formulations and administration routes (Welling, 1996).

Figure 1: Food and Drug Interactions (Polaka et al., 2022).

Drug Instructions Matter

The instructions on a medicine bottle are not arbitrary; they are based on the pharmacokinetics of the drug and how it interacts with food in the digestive system. Taking medications outside of these recommendations can cause an increase in adverse drug reactions, as well changes to the metabolism of the drug. Clinically significant drug interactions can include pharmaceutical, pharmacokinetic, or pharmacodynamic mechanisms of the drug (Bushra et al., 2011). Some drugs may require an empty stomach for optimal absorption. Just like food, orally administered drugs are absorbed into the body through the stomach lining or the small intestine. Therefore, food in the digestive tract may reduce the ability of the body to absorb the drug. Food can also interfere directly with the absorption of certain drugs by delaying gastric emptying or binding to drug molecules, which reduces their bioavailability (Bushra et al., 2011).

Certain foods are known to impact particular medications. For example, monoamine oxidase (MAO) inhibitors, which can be used as antidepressants, have known interactions with foods that are high in tyramine, including matured cheese, ripened bananas, yogurt and salami. Tyramine is an amino acid that usually helps regulate blood pressure, however as it is normally degraded by MAO, taking foods high in tyramine in conjunction with MAO inhibitors causes an overabundance of tyramine in the blood, which can lead to a hypertensive crisis. This is known as the cheese reaction to MAO inhibitors. In light of food-drug interactions, it may be necessary for a doctor to place dietary restrictions on a patient (Bushra et al., 2011).

One of the most infamous foods that can interfere with medications is grapefruit. A multitude of studies have examined this interaction since the phenomenon was discovered completely by chance in 1889, in a study by Bailey et al. (1989) who co-administered felodipine (calcium channel blocker used to treat high blood pressure) and ethanol, using grapefruit juice to mask the taste of ethanol. It was discovered that grapefruit juice dramatically increases the bioavailability of felodipine. Today, more than 85 drugs are known to be affected by grapefruit, and grapefruit juice. Grapefruit affects so many drugs as it inhibits the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many drugs, resulting in elevated blood serum concentration of those drugs. This can lead to dose-dependent adverse side effects and even toxicity (D. G. Bailey et al., 1998). For example, grapefruit juice inhibits the metabolism of some statin drugs, which are used to lower cholesterol. If grapefruit juice is taken while on these statins, the drug will not be metabolised and too much may stay in the patient’s body. This increases the risk of liver failure, kidney failure and muscle damage. Conversely, grapefruit can decrease the bioavailability of some drugs, such as the antihistamine fexofenadine. This drug relies on transporters to allow the active drug ingredients to access the body’s cells. Grapefruit juice can block these transporters and decrease the amount of drug that can reach these cells and can seriously reduce the effectiveness of such drugs (FDA, 2021).

Figure 2: Grapefruit's Effects on Drugs (Hammett et al., 2022).

On the other hand, taking food with medication can be beneficial. Certain medications, including aspirin and some steroids, are harsh on the stomach and can cause irritation to the stomach lining and even ulcers. Taking these medications with some food, such as toast or a glass of milk, can buffer the stomach's acidic environment and help to reduce irritation, which enables the body to better tolerate such drugs. This can also reduce certain side effects, such as nausea or vomiting (NHS, 2023). For some medicines, such as the HIV drug ritonavir, having food in the stomach ensures proper absorption of this medication. A study by Ibarra et al. (2012) showed that co-administration of ritonavir and food increased bioavailability of this drug, as well as reducing physiological differences in the gastric systems of men and women, such as stomach pH and residence time, which meant that the effect the drug in these two sexes could be better predicted.

Bioavailibility

Bioavailability is the extent and rate at which the active ingredients of a drug are absorbed by the body and become available at their site of action (where the drug will exert it’s effect). Food can change the bioavailability of a drug in a wide range of ways. Taking food shortly before or after medication may interfere with tablet disintegration, drug dissolution and drug transit through the gastrointestinal tract, as well as affecting the metabolic transformation of drugs, which mostly occurs in the gastrointestinal wall and in the liver. If food is present, metabolising enzymes cannot break down drug molecules as quickly and the bioavailability of the drug is increased. This can be an advantage or disadvantage (Melander, 1978).

Bioavailability is an important pharmacokinetic parameter and can be correlated with the clinical effectiveness of most drugs. For drugs that are absorbed into the bloodstream, bioavailability is measured from the area under the blood or plasma concentration-time curve (AUC), and the maximum concentration (Cmax). By determining the rate and extent of drug absorption, bioavailability can be used to determine the clinical outcome of a drug, in particular, how quickly a drug will begin to exert its effects (Chow, 2014).

Figure 3: Bioavailability (Le, 2024).

When two different formulations of the same drug (such as a patent and a generic drug, usually produced by different manufacturers) are declared to be bioequivalent, this means that they contain the same active ingredients, in the same amounts, and will provide the same therapeutic effects. Bioequivalent drugs include drugs that are given in the same or similar dose (pharmaceutical equivalents) or in different doses to obtain the same effect (pharmaceutical alternatives). To determine their bioequivalence, the rates and extents of absorption of these drugs must not show a significant difference, so that the active ingredient of the equivalent drug becomes available at the site of action similarly to the first drug, when administered at the same dose and under similar conditions. Appropriate studies must be conducted to determine this equivalency, so that these drugs may be used interchangeably by clinicians. The American Food & Drug Administration (FDA) has strict guidelines on how these studies should be carried out to allow for interchangeable prescription of bioequivalent drugs, including subject selection, length of study and similar insuring conditions for administration of both drugs. As food has such a significant effect on drug absorption, the FDA specifies that for immediate release drugs, the subjects in these studies must be fasted before taking a single dose of the drug. In some cases, they may also require a separate food effect study. For controlled release drugs, where a drug works in a time-controlled manner for a longer period of time, the FDA requires single-dose non-replicate fasting, as well as food effect study before issuing a bioequivalence certification. This is because food can have a greater impact on controlled release drugs (Chow, 2014).

One study by Lukkari et al. (1997) investigated the effects of different time intervals between consuming food and administration of a controlled release tablet of Oxybutynin, which is used to treat incontinence and other symptoms of an overactive bladder. This study measured the blood serum concentration of oxybutynin and its metabolite, N-desethyloxybutynin, over the 48 hours following administration of the oxybutynin tablet under three different conditions: fasted, one hour before a meal or two hours after a meal. The study found that taking this controlled release drug one hour before a meal did not significantly affect the pharmacokinetics of oxybutynin or N-desethyloxybutynin. They also found that taking the drug one hour before food significantly increased the likelihood of consistent drug levels in the blood stream and lowered peak concentration levels throughout the dosage interval. As fluctuations in drug levels and high peak concentrations are associated with adverse reactions, this study suggests that taking an orally administered, controlled release drug one hour before food can improve tolerability and reduce adverse effects of the drug.

Metabolism

Food and drugs are both broken down into molecules that can be absorbed by the body through the process of metabolism. Food is broken into nutrients that keep the body healthy, while drugs metabolism can either inactivate or activate a drug. Usually, drug metabolism is a process to deactivate a drug and break it down so it can be excreted from the body. Most drug metabolism is carried out by metabolising enzymes in the liver through processes including oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization (Le, 2022).

Figure 4: Drug Metabolism (Ha & Bhagavan, 2023).

The rate of metabolism has a serious impact on the performance of a drug: too fast and the concentration of the drug in the blood and tissue may not reach therapeutically effective levels, too slow and the blood and tissue are exposed to a drug for too long and even normal doses of a drug may become toxic. Drug metabolism rates vary between individual patients and can be effected by genetic factors, coexisting diseases (especially liver disorders), and drug-drug interactions. At therapeutic concentrations, most drugs occupy a small amount of metabolising enzymes, and so metabolism rates increase as the drug concentration increases, known as first-order elimination. Most drugs have a specific half-life, which is how the rate of disappearance (following metabolism and excretion) of a drug from the body is measured. Specifically, half-life is the time it takes for the active concentration of a drug in your body to reduce to half of its administered amount. For example, for a drug with a half-life of one hour: if 500 mg is administered, 250 mg will still be in the body after one hour, and 125 mg will still be present after two hours (Le, 2022). Half-life is an important metric used to determine how long the drug will be available in the body, what the steady-state concentration will be, and helps to avoid over-prescription and overdose (Brookfield, 2005).

Conclusion

The food-drug effect has a significant impact on treatment outcomes. The presence of food in the bloodstream while a drug is being metabolized and absorbed can significantly impact the pharmacokinetics, pharmacodynamics of medications. Different foods can have vastly different effects on drugs, depending on their nutritional components. Even when drugs are chemically quite similar, different foods can have completely different, even opposite effects. Consequently, individual clinical studies are necessary to determine the net effect of food on the bioavailability of the specific drug in question (Melander, 1978). Although some food-drug interactions can be used to protect the stomach lining to the benefit of the patient, the food-drug effect is usually harmful and results in adverse effects. Therefore, it strongly advised for patients to follow the drug label instructions, along with directions from their doctor, to obtain the maximum benefits of the drug with as few adverse food-drug interactions as possible.

Bibilography

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Ibarra, M., Fagiolino, P., Vázquez, M., Ruiz, S. A., Sierra, M., Bellocq, B., Perez, M. I., González, B., & Goyret, A. (2012). Impact of food administration on lopinavir–ritonavir bioequivalence studies. European Journal of Pharmaceutical Sciences, 46(5), 516–521. https://doi.org/10.1016/j.ejps.2012.04.004

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