Interactions Between Food And Drugs, And Nutritional Status in Renal Patients: A Narrative Review Ⅱ

2.3. Changes in Resting Energy Expenditure 

Resting energy expenditure (REE) represents approximately 55–70% of the energy requirement in healthy and physically active subjects. REE depends on age, gender, body composition, physical activity, health status, and dietary habits, as well as on the percentage of lean mass and visceral organs. Drugs active on the central control mechanisms (Pro-opiomelanocortin (POMC) neurons and orexigenic neuropeptides Y and AGRP), or peripheral ones (i.e., insulin, cortisol, thyroid hormones) can influence body weight by modulating carbohydrates, lipid,, and protein metabolism. Steroidal anti-inflammatory drugs, estrogen-progestin preparations, and antidiabetic drugs (both oral and injectable ones) affect glucose and/or fat metabolism [28]. Glucocorticoids, in particular, have multiple effects. They can induce insulin resistance, as well as changes in fat-mass distribution, and water and salt retention through residual mineral corticoid activity. 

Estrogens may also impair insulin sensitivity. Interestingly, estrogens promote liver synthesis, circulating HDL and triglycerides with increased uptake and peripheral metabolization of LDL, thus leading to an increased HDL/LDL ratio. Progestins show opposite effects, especially if they have a residual androgenic activity that can be marked weak (desogestrel and gestodene) or purely antagonistic (drospirenone and chlorthalidone) [28].

NEW HERBAL FORMULATION FOR KIDNEY DISEASE

Oral antidiabetic drugs have various mechanisms of action, so they may induce a reduction in body weight (i.e., biguanides, GLP-1 agonists), an increase in body weight (i.e., glitazones, sulfonylureas) or not affect it (i.e., glinides, glitazones, DPP4 inhibitors). In addition, some of them are associated with a risk of hypoglycemia (sulfonylureas and glinides) as well as dysgeusia (biguanides) [29]. Finally, acarbose (an intestinal alpha-glucosidase inhibitor) and SGLT2 (type 2 sodium-glucose transporter) inhibitors may also be associated with weight loss. Antipsychotic drugs of the first (i.e., haloperidol) and the second (i.e., olanzapine, clozapine, and risperidone) generation affect glycemic control, both acting directly on the pancreatic β-cells and on the peripheral tissues inducing insulin resistance. In addition, the sedation effect leads to a reduction in energy expenditure and weight gain, particularly remarkable in adolescents. Antiretroviral protease inhibitors and nucleoside inhibitors of reverse transcriptase (NRTI) may favor weight gain by affecting pancreas β cells [30].

An alteration of glucose metabolism is also found during thiazides and beta-blockers. The former may cause hyperglycemia by reducing insulin secretion secondary to hypokalemia, whereas the latter may induce hyperglycemia, and reduce peripheral insulin sensitivity and weight gain. Table 2 shows the effect of some drugs or classes of drugs on body weight. 

2.4. Drug-Induced Nutrient Deficiency

Micronutrient (i.e., vitamins and minerals) deficiency is another condition of malnutrition, potentially induced by some medications interfering with absorption or excretion. The most common changes are those regarding potassium, sodium, magnesium, iron, calcium, zinc,, and copper. Indeed, some drugs can increase potassium excretion, and sodium retention, or reduce iodine uptake or release, reduce iron and zinc absorption, and increase copper levels. 

Hypokalemia is frequently associated with diuretics (loop and thiazide diuretics), β-adrenergic stimulants, or laxative agents [31], as well as some monoclonal antibodies used in oncology [32]. Hyperkalemia can also occur during therapy with renin-angiotensin-aldosterone system inhibitors (RAASi), namely aliskiren, ACE inhibitors, Angiotensin II receptor blockers (ARB), aldosterone receptor antagonists, β-blockers, nonsteroidal anti-inflammatory agents (NSAIDS), heparins, immunosuppressants (i.e., tacrolimus, cyclosporin), mineral corticoids and glucocorticoids, digoxin [33–36]. 

Hyponatremia is a common electrolytic disorder in people who take medications that act on sodium and water homeostasis, or increase the production/enhance the effect of the antidiuretic hormone (ADH), promoting the reabsorption of water at the level of the renal collecting tubule. Many medications may produce decreased sodium serum levels [37], including thiazide diuretics, SSRIs, antipsychotics such as phenothiazine and haloperidol (which may cause an abnormal secretion of ADH), antiepileptics (i.e., carbamazepine, valproic acid), NSAIDS, proton pump inhibitors (PPI, namely omeprazole and esomeprazole), antineoplastics (i.e., vincristine and cyclophosphamide), and antidiabetics (i.e., chlorpropamide, tolbutamide). 

Several drugs may cause hypomagnesemia [38]. Antibacterial drugs, such as tetracyclines, form an insoluble complex with metal cations; PPI and antacids lower the gastric pH and cause a down-regulation of the active intestinal transporter for magnesium TRPM6, whereas thiazide and loop diuretics prevent magnesium reabsorption-at-the-renal level. Some antineoplastic agents (i.e., cisplatin) and birth control pills cause increased renal excretion of magnesium. Finally, calcineurin inhibitors and iron-based phosphate intestinal binders are also associated with hypomagnesemia [39].

Iron deficiency may be due to reduced absorption, mainly caused by antibiotics such as tetracyclines and quinolones, and gastric antisecretory drugs, i.e., PPI and H2 receptor antagonists [40]. Indeed, gastric acid secretion facilitates the absorption of free iron, allowing its conversion into a ferrous form that is more absorbable than the ferric one; hence, in reducing gastric acidity, the dietary absorption of this mineral is less efficient. A condition of hypocalcemia may be the result of four different conditions [39,41]: hypoparathyroidism, hypovitaminosis D, calcium-binding agents, or impaired bone resorption. Medications most often associated with hypocalcemia are loop diuretics (for increased calcium excretion), chelating agents (i.e., ethylenediaminetetracetate, citrate, phosphate), antineoplastic drugs (i.e., cisplatin, leucovorin, 5-fluorouracil, nab-paclitaxel, axitinib), biphosphates, calcitonin and denosumab (a monoclonal antibody used to treat osteoporosis). 

Drugs that may facilitate copper and/or zinc excretion generally contain sulfhydryl groups, such as propylthiouracil and methimazole, captopril (an ACEi), and penicillamine (used in Wilson's disease, rheumatoid arthritis, etc.) [42]. Interestingly, these drugs may cause also dysgeusia. 

Common changes in vitamin availability may affect thiamine (B1), niacin (B3) and pyridoxine (B6), folate, together with vitamins B12, C, and D. Drugs that may cause vitamin B deficiency (in particular B12, B6, and B3) are mainly diuretics (they increase vitamins B removal, B1 in particular) and fibrates. Anti-acids such as H2- antagonists and PPI may decrease vitamin B12 absorption by reducing gastric acidity [43]. Vitamin B12 deficiency may also occur with acetylsalicylic acid (ASA), antipsychotics (i.e., trifluoroperazine), colchicine, estrogens and metformin [44]. A reduction in vitamin B6 and vitamin PP levels may occur during treatment with antidepressants, particularly SSRI, and some antitubercular drugs (i.e., isoniazid). Folate deficiency may be caused by some antibiotics (penicillins, cephalosporins, tetracyclines), fibrates, birth control pills, ASA and antirheumatic drugs (namely Methotrexate), some chemotherapeutics, oral antidiabetics (in particular biguanides, and sulfonylureas), anticonvulsants (i.e., phenytoin, phenobarbital, primidone) and neuroleptics (phenothiazines). 

Drugs able to cause vitamin C deficiency include diuretics, birth control pills, and ASA. Among the fat-soluble vitamins (A, D, E, and K), the deficiency in vitamin D is the more prevalent and may be caused by drugs such as statins, antacids, anticonvulsants (i.e., phenytoin), cholestyramine, glucocorticoids, and sevelamer, an intestinal phosphate binder [45]. Coenzyme Q10 (ubiquinone) is fundamental for the proper functioning of mitochondria. Some drugs can interfere with its function, as in the case of antidiabetic drugs (biguanides, metformin, and in particular sulfonylureas glyburide and tolazamide), β- blockers, statins, corticosteroids, warfarin, and diuretics (i.e., acetazolamide). 

3. Interaction between Food and Drugs

The possible interactions between food and medications are relevant in clinical practices [46], but often unknown or overlooked. They occur more frequently with orally administered drugs [47]. Indeed, food and beverages may alter the pharmacokinetic and pharmacodynamic profiles of a drug, leading to two different conditions: 

(1) Increased concentrations in biological fluids that could enhance drug effect, up to the risk of side effects and toxicity;

(2) Reduced concentrations in biological liquids, and thus reduced effect of the drug, with the risk of total or partial ineffectiveness.

The first point to be considered is that interactions and their severity should be known and prevented, to avoid the risk of toxicity or therapeutic ineffectiveness. Indeed, although many interactions are hypothetical, some of them can be clinically evident or can be classified as real adverse drug reactions (ADR). ADRs are unintentional adverse reactions caused by a drug, and in the case of interactions with foods, they may have the characteristics of toxicity or therapeutic failure.

It is necessary to distinguish three factors that potentially increase the risk of serious interactions: the type of drug involved in the interaction, the severity of the disease for which the drug is administered, and the general conditions of the patient [20,48]. Drugs with a low therapeutic index can be involved in clinically evident interactions due to the narrow range between efficacy and safety since adverse events can appear at doses normally used for therapy. Hence, even small changes in blood or plasma concentrations of a drug with a narrow therapeutic range may result in toxicity or therapeutic failuresImmunosuppressive drugs (calcineurin or mTOR inhibitors), medications active on the cardiovascular system (antiarrhythmic drugs, cardioactive glycosides, oral anticoagulants and on the respiratory system (i.e., theophylline) are examples of pharmacological agents with a low therapeutic index [49-51]. Drugs active on the central nervous system (such as antidepressants, anxiolytic-hypnotics, mood stabilizers, and antiepileptics) may also be included in this group. Moreover, medications administered for chronic diseases expose patients to a greater risk of interactions because of the long-term administration second factor is the severity of the disease for which the medications are required; for example, anti-coagulant therapy puts the patient at risk of hemorrhagic or thrombotic complications, in cases of over-dosage or under-dosage, respectively [50]. Similarly, a patient may risk the rejection of the transplanted organ or the onset of toxicity in the case of an interaction withimmunosu!  oppressive drugs.

The third tractor is identifiable in the general condition of the patient. For example advanced age may be associated with cardiovascular or metabolic comorbidities, which may negatively affect drug-liver biotransformation and renal excretion [50]. The possible alteration of the absorption rate may be also caused by changes in intestinal motility, different body composition (i.e., reduction in fat tissue mass), and, above all, the reduced capacity of the organism in critical conditions to metabolize drugs and to eliminate them in stool or urine. The main food and drug interactions are summarized in Table 3.

Table 3. Food–drug interactions. Foods to avoid or not to take in conjunction with medications, due to the risk of severe interference with drugs. 

4. Pharmacokinetics Basis of Food-Drug Interactions 

Pharmacokinetic interactions concern the processes of absorption, distribution, metabolism, and elimination. In addition to single foods or nutrients, even the meal as a whole can significantly affect the pharmacokinetics of the drug, by changing its safety and therapeutic efficacy [52–54]. Moreover, the different pharmaceutical forms in which the active ingredient is administered and the different chemical and physical characteristics, such as solubility or permeability along the gastrointestinal tract, may cause the drug to be differently affected by the food.

In general, among the four pharmacological processes, food can mainly interfere with absorption and metabolism. Indeed, the alterations of these two processes can change the effective bioavailability of the drug (i.e., the percentage of a dose of the active drug that is found in the body after its administration). After an oral administration, the drug takes about 1–2 min to reach the stomach, where it dissolves, and part of the active ingredient passes into the bloodstream. The remaining part transits into the intestine, where the absorption is completed. The presence of a certain type of food may lead to a chemical-physical interaction, consisting of the formation of the molecular bond between the food and its component, and the active part of the drug. Consequently, this type of interference causes a decrease in drug absorption. Another mechanism is based on the modification of the physiology of the gastrointestinal tract [53], which occurs as a result of food ingestion, reduction in gastric acidity, increased gastric emptying times, changes in bile secretion, increased intestinal motility and alteration of the gut microflora composition. All of these alterations can finally change the absorption rate of a drug

5. Changes in Drug Bioavailability 

Drugs that are weak acids are absorbed at the stomach level, whereas weak bases are preferably absorbed at the small intestine level. Both chemical and physical properties may influence the absorption phase of drugs, such as the dissociation constant [55], a pH-sensitive parameter influenced by the formation of bonds and/or complexes with other molecular entities. Therefore, the introduction of a food that causes a change in the pH within the gastrointestinal tract, especially at the gastric level, can affect the ability of the drug to be absorbed. In addition, bonds and/or complexes may be formed between the drug and some molecules or ions contained in the food. Alteration of drug absorption by a food or a meal can also occur by binding of the active ingredient with the drug carrier protein; the competition between food and drugs for the binding with transport proteins can limit the absorption of the pharmacological agent. 

Along the gastrointestinal tract, pH, perfusion, absorbent surface per unit volume and motility may influence the absorption rate of drugs in different ways [56]. For example, the gastric emptying time and the intestinal transit time are two factors that participate in the successful administration of the drug [57]. In particular, the ingestion of solid foods, especially if warm, viscous, and rich in fat, causes a slowing of gastric emptying times and therefore a delay in the absorption of the drug at the intestinal level, even if the total amount of drug absorbed is unchanged. Furthermore, the ingestion of solid food stimulates the production of gastric bile, and pancreatic juices, which generally improves the dissolution of the drug and facilitates its absorption [58]. Meals with a high lipid content stimulate a greater production and release of bile in the duodenum, favoring a greater absorption of those drugs that need bile salts for optimal absorption. Interestingly, some drugs conjugated with glucuronic acid undergo an enterohepatic circulation that ensures a longer presence within the bloodstream and the tissues [59]. 

6. Changes Due to Fluids, Protein, Lipid and Fibers Intake 

Fluid intake can affect the absorption of a drug. Indeed, the volume and the temperature of beverages may alter the transit of the drug through the stomach, so modifying the time necessary for the appearance of the pharmacological effect [60]. Except water, the intake of any beverage in conjunction with the drug could lead to a different absorption of the latter. Namely, there could be changes in the gastric pH, a delay of gastric emptying or chelation reactions, or the prevention of drug absorption. For example, this occurs with cola, cocoa, coffee (caffeine), and milk [61,62]. Moreover, the use of water for taking drugs prevents the adhesion of the drug to the esophagus and stomach wall and allows a rapid transit to the absorption site. Attention should be paid to the fluid temperature: hot or too-cold water should be avoided, because in both cases the gastric emptying time may increase. 

Meal composition may affect the absorption of the drug in several ways. A high content of amino acids derived from high protein meal can form bonds with the drug or can compete with it for binding to the transport carriers [63]. Moreover, the increased secretion of pancreatic juices may cause an augmented quantity of water at the intestinal level, leading to drug dilution. On the other hand, a protein-rich meal increases blood supply to the intestine, facilitating and speeding up the absorption of the drug. A meal rich in lipids delays gastric motility and increases bile production [64]. This kind of meal helps in the absorption of the so-called "lipophilic" drugs. On the contrary, the fiber content of a meal increases gastrointestinal motility and reduces intestinal transit time. As a consequence, the bioavailability of drugs is reduced, together with their pharmacodynamic effects.

A special case of food–drug interference occurs between the intake of foods rich in tyramine (monoamine resulting from the amino acid tyrosine) and IMAO drugs, causing an excessive accumulation of monoamines that results in an acute increase in blood pressure and headaches. In this case, the diet should limit the intake of hard cheeses, beef, processed meat, yeast extract, dried fruit, soya, chocolate, etc. It is also important to pay attention to the intake of tyramine during treatment with linezolid, a drug used to treat severe infections. Indeed, linezolid acts as a MAO inhibitor, so its concomitant administration with foods rich in tyramine may cause a sudden increase in blood pressure. Another important factor is the time between the administration of the drug with respect to the meal or food intake [65]. The drugs most sensitive to these interactions are mainly those unstable in gastric fluids or that are more likely to form bonds with food molecules. For this reason, the drugs are divided into two main categories: drugs that must be taken with a meal or in conjunction with a meal (administered in the half hour before or after the meal) and drugs that must be taken without food, namely about 2 h before or 3–4 after the meal.

7. Changes in Drug Distribution 

Several factors influence the volume and speed of drug distribution, depending on the tissue in which the drug is distributed and the chemical-physical characteristics of the drug, so that the percentage of fat and lean mass of the subject affects the rate of distribution of a drug, its half-life and the time needed to reach the steady state, in both adult and pediatric patients [66]. The pharmacokinetics of the lipophilic drug is mainly dependent on the adipose body mass. Fat tissue is poor in water (especially intracellular), and scarcely vascularized. Lower water content causes a lower distribution of hydrophilic drugs in the adipose tissue and a greater distribution of lipophilic ones [67]. On the contrary, hydrophilic drugs administered in overweight or obese subjects, who have a higher percentage of adipose body mass, are distributed in a lower volume of water. Therefore, the calculation of the dose based on actual body weight may expose the subject to the risk of overdosing, because the quantity of fluids in which the drug is distributed is not proportional to body weight. As a result, the drug will have a higher plasma concentration longer half-life, and presumably greater effects than expected, even if that rule may not be true for all drugs [68,69]. An additional factor influencing drug distribution is represented by the binding with plasma proteins because only the free form of the drug can spread within the extra-vascular space or within the cells where it exerts its effects. Of note, albumin binds acidic drugs, whereas acid alpha-glycoprotein and lipoprotein basic drugs, combined with several factors (i.e., liver and renal diseases, inflammation, cancers), may affect the concentration of plasma proteins available for drug binding [70,71].

Changes in body composition occur not only in the case of overweight/obesity, or lean-body-mass reduction but also in extreme age ranges. Indeed, both in newborns and the elderly, body composition is quite different than in adults. In newborns, there are high percentages of body water (75–80% approximately) and low percentages of fat mass, whereas in the elderly there are physiological reductions in body water and an increase in adipose tissue [72,73]. With advancing age, there is also a lower binding capacity of plasma proteins (namely, hypoalbuminemia), a lower plasma volume, reduced enzymatic activity, and decreased kidney function. This leads to an alteration in the distribution volume of drugs: in older patients, water-soluble drugs have a lower volume of distribution, while fat-soluble drugs have a higher volume of distribution with respect to body weight. 

8. Changes in Drug Metabolism 

It is worth noting that drugs, nutrients, and food may affect the activity of liver enzymes, resulting in an increased or decreased metabolism of drugs, and consequently in a diminished or augmented pharmacological effect, respectively. The CYP450 isoforms (namely, CYP3A4,5,6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) are the most important enzymes involved in drug biotransformation. 

In particular, the intake of certain foods (i.e., soy) or beverages (i.e., grapefruit and blueberry juice) may inhibit the activity of cytochrome P450 enzymes, thereby altering the concentration of the drug at the level of the target site of action [74]. In the case of grapefruit juice, the inhibition lasts for several hours and hepatic CYP3A4 activity returns to normal within 48 h from the intake of the juice [75]. It is clear that the risk of a food–drug interaction, which could be clinically relevant, may depend on the safety of the drug (i.e., therapeutic index), the duration of the concomitant intake of both the drug and the food, and, finally, on the clinical conditions of the patient and the severity of the disease. Furthermore, a diet that is high in protein and lipid content but poor in carbohydrates is capable of inhibiting the CYP450 activity, and consequently of increasing the plasma concentration of the drug. This inhibition is particularly severe for long, unsaturated chains of fatty acids [76].

9. Changes in Drug Elimination 

The kidney is primarily responsible for the elimination of most drugs, through glomerular filtration and tubular secretion. It is worth noting that the free fraction of the drug that is filtered by glomerulus can, however, be rapidly reabsorbed at the tubular level, if it is in the non-ionized form. The weak acid or base character of the drug explains the equilibrium between the dissociated and undissociated form that is dependent on the pH of the ultrafiltrate, and consequently the final excretion or the reabsorption of the dissociated or undissociated forms of the drugs, respectively. Therefore, all those foods or beverages that can acidify or alkalize the urine, can then alter the resorption and facilitate the excretion of certain medications. An example is the so-called alkalizing or acidifying diets [77]. An alkaline diet is characterized by the presence of vegetables and fresh fruit and a reduced intake of acidifying foods; it is rich in sulfur, phosphorus, and chlorine, contained in foods such as cheese, meat, sausages, eggs, simple sugars, refined flours, coffee, and tea. On the contrary, in the acidifying diets, the intake of proteins of animal origin is high, and low in fruit, vegetables, and pulses (the so-called Western diets). The acidity or alkalinity of food can be defined by the PRAL index (Potential Renal Acid Load): foods with negative PRAL are potentially alkalizing, whereas those with positive PRAL are acidifying [77]. Some foods are "neutral", or slightly acidifying, such as whole grains, legumes, milk, and dried fruit. 

10. Pharmacodynamics and Pharmacokinetics of Food-Drug Interactions 

An analysis of the scientific literature showed that scarce attention is addressed to the investigation of food–drug interactions. Moreover, food contains so many compounds capable of interfering with drugs that it is difficult to investigate all of them [78]. Another explanation is that the concentrations of food constituents and nutrients capable of altering drug pharmacodynamics depend on multiple variables, such as the type of fruit/vegetable, the geographical origin, the harvest season, the degree of maturation of the fruit/vegetable, and storage conditions [79]. For this reason, most studies have been focused mainly on food supplements and drinks, or extracts such as fruit juices, teas, herbal teas, alcoholic beverages, coffee, and milk. 

11. Vegetables Rich in Vitamin K 

Among the best-known drug-food interactions, the association of warfarin with foods rich in vitamin K is certainly the best known. The warfarin effect is due to the incomplete synthesis of coagulation factors, through the γ-carboxylation of glutamic acid residues, for which vitamin K plays an essential role. Foods rich in vitamin K may interfere with the therapeutic effect of the drug. These foods are mainly represented by crucifers (broccoli, cabbage, etc.), lettuce, spinach, parsley, etc. High vitamin K content may be found also in asparagus, peas, lentils, soy, egg yolk, liver, etc. Despite this risk, patients on warfarin treatment may eat those vegetables, paying attention to eating a moderate quantity over a long time, eating the same amount daily, and adjusting the warfarin dose consequently. A recent meta-analysis reported that the restriction of vitamin K intake does not seem to be a useful strategy to improve the efficacy of warfarin [80]. Several studies have found a negative relationship between vitamin K intake and variations of the international normalized ratio (INR), while others have found a positive, but dose-dependent, relationship: with a minimum intake of vitamin K, it is still possible to maintain adequate anticoagulation effect. If the intake exceeds 150 µg/day of vitamin K, the effect of the drug is altered [80]. Therefore, a useful approach to overcome this problem is to maintain a stable dietary habit, avoiding wide changes in vitamin K intake [80,81]. 

12. Goitrogenic Foods

Another well-known food-drug interaction is between levothyroxine and so-called goitrogenic foods, which include crucifers (cabbage, cauliflower, broccoli, etc.), soya, lettuce and spinach, milk and some additives such as nitrites. These foods can interfere with the metabolism of iodine which is essential for the proper activity of the thyroid gland through the synthesis of T3 and T4 thyroid hormones [82]. Indeed, the high concentration of isothiocyanates in these foods can inhibit the incorporation of iodine and therefore the formation of thyroxine, decreasing thyroid function [83]. However, in the majority of cases, this does not imply the complete exclusion of these foods from the diet. It is possible to consume them, paying attention to the amount, frequency, and time of consumption. In any case, patients may have these foods occasionally, in moderate servings and not earlier than 30–60 min from the intake of levothyroxine. 

However, some of these interactions have not been confirmed, as in the case of soya twhichmay increase the risk of hypothyroidism. A recent systematic review has shown that eating soya does not affect thyroid hormones and may result in a modest increase in thyroid-stimulating hormone (TSH) levels [84]. Therefore, in the context of a varied diet, it is possible to consume soya in subjects with thyroid problems, provided that the diet is not deficient in iodine. Special care should be taken in the case of Hashimoto thyroiditis treated with levothyroxine, because soy can interfere with this drug. However, a soybean intake at least 4 h away from the drug can be considered harmless [84]. 

13. Fruit or Vegetable Juices

Grapefruit, orange, apple, pomegranate, blueberry, and tomato juices have been investigated for their potential interactions with medications. Among all fruit juices, grapefruit juice is the best known [85]. It is a potent inhibitor of the activity of some isoforms of the cytochrome P450 active in the intestine, CYP3A4 isoform in particular, which is responsible for the detoxification of about 50% of drugs. This inhibitory activity is due to some substances contained in the grapefruit and its juice, namely the naringin (a phenolic compound with anti-inflammatory and antioxidant properties) and the bergamot tine (furanocoumarin). The list of medications that can be affected by grapefruit juice is long, and includes commonly prescribed medications such as [86]: 

Flavonoids contained in grapefruit juice, such as naringenin and hesperidin, are responsible for the inhibition of transmembrane transporters, which play a role in the passage of the drug from the intestinal lumen within the bloodstream. These compounds are also present in other fruit juices, such as citrus fruit juices. Indeed, orange, apple, kiwi and papaya juices, which contain the same flavonoids (naringine, hesperidine, and floridzin, floretin) are able to inhibit the transport polypeptides of organic anions (OATP) at the usual doses. Namely, 1–2 fruits of standard size or 200 cc of commercial or homemade juice are enough to inhibit this process [79,87–89]. The intake of these fruit juices determines the reduction in gastrointestinal absorption of certain antibiotics, antihypertensive, beta-blocker and antiallergic drugs. In particular, the coadministration of drugs such as acebutolol, celiprolol or fexofenadine with grapefruit juice, or atenolol, ciprofloxacin, and fexofenadine with orange juice, decreases the oral bioavailability of antihypertensive and anti-histaminergic drugs [90]. 

Some studies suggested that aloe juice could reduce the effectiveness of some chemotherapeutic drugs, although it may increase the effect of oral antidiabetics due to a further decrease in blood glucose levels when aloe juice is taken with those drugs. The Aloe juice should not be taken with medications such as thiazide diuretics, glucocorticoids and cardioactive glycosides, to avoid the risk of increased renal potassium excretion leading to hypokalemia [95]. Pineapple juice or its extracts can interact with NSAIDs, warfarin, antiplatelet agents and heparin, causing an increased risk of bleeding. Vegetable juices such as cabbage, onion and green pepper juices have proven to be able to competitively inhibit CYP3A4 activity [93]. However, those inhibitory effects were not tested in vivo, and the number of flavonoids contained in those vegetables is dependent on the growing conditions, so it is not possible to conclude with certainty that cabbage and onion can inhibit CYP3A4 activity at a clinical level [94]. Tomato juice contains one or more competitive direct inhibitors of CYP3A4 activity [96]. This effect has also been observed in other solanaceous plants, such as potatoes, eggplants, and peppers; therefore, it is believed that these vegetables share the same inhibitory compounds [97].

Overall, these studies bring further important information. First, fresh or homemade juice is less likely to inhibit drug uptake than commercial juice. Second, it has been illustrated that the reduction in drug uptake is directly proportional to the amount of juice consumed and to the time between juice and drug intake [87]. In general, it has been observed that a period of time of four hours between the consumption of juice and the intake of the drug is recommended to avoid any chance of interaction [87]. These studies have several limitations, the most important one being that they have been carried out in vitro. Few studies have investigated drug–food interactions in vivo, and rarely in humans [91]. The short exposure to food and nutrients, usually lasting two weeks, could explain the lack of clinical trials [98,99]. 

#cistanche #cistanchedeserticola #cistanchetubulosa #cistanchesalsa #glycoside #echinacoside #verbascoside #acteoside #ニクジュヨウ #肉蓯蓉 #ベルバスコシド #アクテオシド #クサギニン #エキナコシド

Supportive Service Of Wecistanche:

Email:wallence.suen@wecistanche.com 

Whatsapp/Tel:+86 15292862950