C. Food-related prescription warnings

Many prescription medications contain warning labels to avoid consumption of specific beverages, foods or supplements within a range of time around dosing. This section expands warning information with mechanisms underlying common warnings.

Take with food/ Take without food

The most common food-related prescription warnings you may notice are related to taking drugs with or without food. Some drugs should be taken with food to help improve adherence to a therapeutic plan, to avoid GI upset, or to improve drug absorption. Interestingly, taking medication with food can increase or decrease its bioavailability, depending on a drugs’ lipid solubility and other factors.^[1] Some drugs should always be taken without food in order to be properly absorbed from the GI tract; some generic examples include Zithromax, Flagyl, Lasix and Ambien.^[2]

Grapefruit juice

Grapefruit juice is perhaps the best-known drug-food interaction. Grapefruit juice contains furanocoumarins and other substances that inhibit CYP3A and other CYP isoforms.^[3] As discussed in part B, CYP enzymes hold primary responsibility for processing/metabolizing drug compounds during Phase 1 metabolism. As a result, drugs that are absorbed by the intestines and metabolized by CYP3A can be significantly affected by grapefruit juice. Grapefruit juice that is reconstituted from frozen concentrate or diluted from concentrate have also been shown to interact.^[4] Segments from unprocessed grapefruit are also reactive. In short, any form of grapefruit should be considered to produce a drug interaction. Importantly, even small amounts of grapefruit or grapefruit juice (200 mL, or less than 1 cup) is sufficient to produce this effect.^[5] The drug interaction caused by grapefruit juice has a lengthy duration. For example, grapefruit juice consumed today could impact the oral bioavailability of a drug administered tomorrow. As a result, it is recommended that grapefruit juice consumption should best be avoided entirely during pharmacotherapy, rather than within hours of drug administration.^[6] A patient’s pre-existing medical conditions affects susceptibility to grapefruit juice and drug interactions. For example, dihydropyridines produce a blood pressure-lowering effect that is dependent on pretreatment blood pressure. (They are known L-type Calcium channel blockers, used in the treatment of hypertension.) The greatest reduction in blood pressure occurs in patients with the highest pretreatment blood pressure.^[7] Age is also a concern that can affect susceptibility to drug interactions. Elderly patients have demonstrated an enhanced antihypertensive effect to dihydropyridines compared to younger individuals. The elderly are most often prescribed medications and major consumers of grapefruit juice; as a result, the potential for an unwanted grapefruit juice – drug interaction in this population is substantial.^[8]

A formal clinical study involving patients with untreated borderline hypertension established the grapefruit juice and CYP3A reaction. The peak concentration (Cmax) and area under the plasma drug concentration -time curve (AUC) of felodipine (a dihydropyrine, mentioned in the above paragraph) were essentially three-fold to the same measurements when dosed with orange juice or water.^[9] This pharmacokinetic drug-nutrient interaction is only seen with orally dosed medications. In the clinical study mentioned above, intravenously (IV-) administered felodipine with grapefruit juice was unaffected. The mechanism underlying this drug-nutrient interaction is reduced activity of felodipine metabolism, which is mediated by CYP3A4, during first-pass.^[10] Researchers have noted that administration of just 250mL of grapefruit juice causes a mean 62% reduction of enterocyte CYP3A4 protein content. Liver CYP3A4 activity was not altered. This provides clear evidence for the gastrointestinal (GI) tract as a central site of drug metabolism.^[11]

Cruciferous vegetables

Cruciferous vegetables are rich sources of a variety of interactive dietary components. Classic examples are Vitamin K-rich kale, cabbage and Brussels sprouts. Other interactive dietary components in cruciferous vegetables include indoles, including indole-3-carbinol and indole-3-acetonitrile.^[12] These vegetables and indoles have effects on the metabolism of environmental carcinogens such as aflatoxin B1 and binding of their metabolites to DNA. In other words, consumption of cruciferous vegetables has been shown to mitigate cellular damage associated with environmental contaminants and cancer-causing agents.^[13] These findings led to research aimed at investigating the impact of cruciferous vegetables on drug oxidation and conjugation in normal, healthy patients on prescriptive diets.

Clinical research studies investigating the capacity of cruciferous vegetables to impact drug metabolism have demonstrated that cruciferous vegetables (Brussels sprouts and cabbage) significantly enhance the oxidative metabolism of antipyrine, phenacetin, and the conjugation of acetaminophen.^[14] Watercress is also a cruciferous vegetable and contains a glucosinolate precursor of phenethyl-isothiocyanate, which can impair CYP2E1 activity and the metabolism of drugs such as chlorzoxazone.^[15] In clinical research studies investigating watercress and drug metabolism, a single ingestion of watercress increased the area under the chlorzoxazone plasma concentration time curve by 56% and prolonged the chlorzoxazone elimination half-life by 53%.^[16] The magnitude of this effect is similar and somewhat greater, respectively, compared to those seen with an established CYP2E1 inhibitor, isoniazid. Watercress has also been shown to reduce peak plasma concentration and area under the plasma concentration-time curve for oxidative metabolites of acetaminophen (the active ingredient in Tylenol).^[17]

Alcohol

You may have noticed prescription warnings “Avoid or limit alcohol consumption” on labels and drug information. Specific drugs can elicit mild to severe adverse drug reactions when taken with or during alcohol use. One extreme examples of alcohol-drug interaction are seen in tetraethylthiuram disulfide (disulfiram).^[18] Adverse reactions develop soon after alcohol is consumed in patients taking disulfiram. As a result, disulfiram is used to treat chronic alcoholism. The drug has been used in alcohol treatment programs as an adjunctive means of encouraging alcohol abstinence.^[19] Unpleasant manifestations of the alcohol-disulfiram reaction include flushing, headache, nausea, vomiting, weakness, vertigo, blurred vision and seizures. Disulfiram inhibits the enzyme aldehyde dehydrogenase, which oxidizes acetaldehyde that is derived from alcohol.^[20]

Cephalosporin antibiotics are also known to interact with alcohol. These antibiotics have differing effects on liver alcohol dehydrogenase and circulating acetaldehyde levels. Cephalosporin drugs reported to cause disulfiram-like reactions include cefoperazone, moxalactam, ceftriaxone, cefonicid, and cefmetazole.^[21] All of these except ceftriaxone have been pulled from the US market because of these issues. Metronidazole (Flagyl) might be the most prominent antibiotic in this family that remains available, with a disulfiram-like reaction.  The mechanism underlying this drug reaction is not enzyme inhibition, but reactive metabolites. Drugs with a very specific chemical structure are associated with this type of unfavorable reaction (drugs with a N-methyl-tetrazole-thiol side chain in the 3’-position).^[22] Moreover, drugs with this type of structural feature can also inhibit vitamin K epoxide reductase (VKOR) and cause coagulopathies (hypoprothrombinemia and bleeding), particularly in patients with vitamin K deficiency. Vitamin K supplementation can prevent this drug-induced condition.^[23]

Caffeine

Caffeine is a common, natural, non-nutritive methylxanthine component of foods and several beverages such as coffee and tea. It is also added to many popular carbonated beverages. Caffeine is extensively metabolized by CYP enzymes. When caffeine is taken regularly, it can accumulate and influence drug metabolism.^[24] Caffeine’s effects on drug metabolism are complex and may involve saturation, inhibition, or induction of liver enzymes that metabolize methylxanthines and other drugs and chemicals.^[25]

Clozapine is metabolized by CYP1A2 enzymes (similarly to caffeine) and is used in the treatment of schizophrenia.  In a clinical research study evaluating the impact of caffeine withdrawal on clozapine treatment, it was found that clozapine concentrations were lower after changing to a caffeine-free diet for 5 days.^[26] Therefore, habitual caffeine intake can alter the metabolism of clozapine. As a result, caffeine intake should be medically supervised and clozapine levels monitored when this medication is prescribed for schizophrenic patients.