Phytochemicals That Interfere With Drug Metabolism and Transport, Modifying Plasma Concentration in Humans and Animals.

Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.

Introduction

In recent decades, the quality of dietary and lifestyle habits has changed substantially compared to the second half of the twentieth century. In today’s society, the intake of organic foods and food supplements has significantly increased as a result of the generalized concern about healthy lifestyles and disease prevention. The use of dietary supplements continues to increase every year among patients interested in “natural” remedies. It is estimated that the consumption of dietary supplements increased by 42% in people over 20 years of age between 1988 and 1994. Half of the USA adult population has reported using at least one dietary supplement.

The interaction between drugs and food, such as fruits, vegetables, roots, tubers, honey, olive oil, drinks, wine, tea, and chocolate, has begun to attract the attention of researchers due to compounds present in food that can interact with the enzymes that metabolize and excrete drugs. This occurs because of the similarity in chemical structure between some food compounds and drugs.[2-4] With increasing frequency, medications prescribed by physicians interact with food products, mainly in patients undergoing chronic therapy.[2,5] Until a few decades ago, these interactions were not suspected.

Cases of therapeutic ineffectiveness and adverse drug reactions have been reported as a consequence of the interaction between medications and plant products consumed as an alternative herbal medicine or nutritional supplements. This type of interaction happens whenever the effect of a drug is altered as a result of previous or simultaneous administration with a plant product or nutrient.[3-5]

The influence of dietary components on the effect of drugs depends on numerous variables, including the physicochemical properties and the biological, clinical, and cultural characteristics of the patients, such as age, sex, genetic background, diet quality and dietary patterns, nutritional status, etc.

Food-drug interactions can manifest as changes in the blood levels of drugs due to alterations in the processes of absorption, distribution, metabolism and excretion.[5,7] It has been reported that some plant molecules phytochemicals (Pch) interfere with the modulation of the expression and activity of cytochrome CYP3A and P-gp, changing the pharmacokinetics of drugs. The National Health and Nutrition Examination Survey reported that the most widely used nutritional supplements in the US are coenzyme Q10, cranberries, echinacea, fish oil, garlic, ginseng, Ginkgo biloba, glucosamine/chondroitin, green tea, melatonin, methylsulfonylmethane, milk thistle, probiotics/prebiotics, saw palmetto and valerian. Therefore, it is relevant to study how Pchs consumed in the diet can interact with the metabolic and drug transport processes.

Based on the above the purpose this review focuses on the importance os Pchs present in food and nutrients in the daily diet, which can either inhibit or promote the action of cyp3a/CYP3A and abcb1/P-gp, and the role they have with the metabolism and transport of drugs.

Methods

A systematic review without meta-analysis was conducted in biomedical databases, including the Cochrane Library, Embase, Medline (PubMed), Lilacs, and Web of Science to identify articles providing evidence of phytochemical-drug interaction in preclinical and clinical studies. Likewise, those in which the AUC of the drug alone and in co-administration with Pchs. Additionally, a complementary review was carried out in the same databases to establish which Pchs are present in the plants.

Inclusion criteria: Studies published between 2000 and 2021, no language filters were applied, and the following MeSH terms were used: phytochemical, herb, food, nutrient, drug, AUC, drug concentration, modification, induction, inhibition, CYP3A, P- gp, expression of the cyp3a, abcb1 genes. Excluded manuscripts did not report the pharmacokinetic value of AUC or their results did not show significant differences between controls and co-treatments; duplicate articles were also removed.

Thus, one hundred and thirty-one results were obtained through the search in the databases. After critical reading, 54 articles were included and 77 were eliminated because they did not report the AUC or did not present significant differences between the control and the co-treatment. The remaining 123 articles correspond to the complementary review of the phytomolecules present in plants. Total of 177 articles were included in this review.

Cytochrome

Cytochrome (CYP) is an enzymatic system of heme proteins that catalyze the oxidative metabolism of a large number of exogenous and endogenous compounds.[9-11] Cytochromes are constitutively expressed in the endoplasmic reticulum of hepatocytes and various extrahepatic tissues, including the intestine, kidney, lung, skin, adrenal cortex, testes, placenta, and various brain regions.[10-14]

The main function of CYP is to transform poorly soluble (lipophilic) xenobiotics into water-soluble (hydrophilic) metabolites to accelerate urinary excretion.[3,10] It metabolizes a large number of medications, including neuropsychiatric, antineoplastic, cardiovascular, immunosuppressive, antibiotic, antiviral, and antifungal drugs. The most important property of CYP is that it can be induced and/or inhibited by xenobiotics, including drugs.[10,13] CYP3A is a genetically conserved enzyme. For this reason, it has very little genetic variability and a low frequency of polymorphisms. However, it should be noted that the expression of CYP3A could be affected by exogenous compounds present in different foods and herbs consumed in the daily diet.[5,10,15-17]

P-Glycoprotein Transporter

P-glycoprotein (P-gp) is a protein encoded by the abcb1 gene (Multridrug resistance 1 or MDR1), which belongs to the group of adenosine-triphosphate binding cassette (ABC) transporter genes. It is a membrane protein whose function is to protect cells through the expulsion of unknown toxic substances. P-gp also contains multiple binding sites for xenobiotics (including drugs), and it is capable of simultaneously binding to multiple substrates at overlapping binding sites.

This transporter is highly expressed in tissues that have direct contact with xenobiotics, such as the epithelium of the gastrointestinal tract, the proximal renal tubule, the pulmonary bronchi, the canalicular surface of hepatocytes, and the surface of the endothelial cells of the blood-brain barrier. Since drugs are expelled from these tissues, P-gp helps to reduce the systemic concentration of drugs.

Due to the importance of P-gp in the transport and excretion of drugs, the concomitant administration of any drug, food, and/or medicinal herb that modifies the expression and activity of P-gp can have important pharmacological consequences[7,20] regarding the concentration and bioavailability of administered drugs.[21-27]

Interaction Mechanisms

The mechanisms that affect the drug concentration can involve the modulation of cyp3a/abcb1 (gene activation or repression) or inhibition of CYP3A and P-gp proteins.[9,11]

Gene Expression (Activation or Repression)

Activation of gene expression by Pchs can be done through nuclear receptors such as PXR, PXR is a transcription factor (TF) found in the cytoplasm, Pch as hyperforin can act as a ligand and binds to PXR, this allows that the ligand-TF complex translocates to the nucleus and transcribes target genes such as cyp3a and abcb1. In repression, Pchs like flavonoids, decrease the mRNA levels of CYP3A and P-gp by unknown mechanisms (Figure 1).[28-41]

Figure 1.

Mechanisms involved in the modulation: (1) Some Pch such as hyperforin and some flavonoids modulate cyp3a and abcb1 gene expression by activation or repression modify mRNA transcription for CYP3A and P-gp.[8,31,35,93,94] However, the exact mechanism by which the repression of both proteins is carried out is unknown.[11,31,95] (2) Flavonoids such as bergamottin and other Pchs bind competitively or noncompetitively to CYP3A and P-gp proteins,[96,97] resulting in inhibition of the activity of both proteins. Both mechanisms result in changes in blood concentration of drugs and prodrugs.

Inhibition of Protein Activity (Metabolism or Transport)

Some Pchs inhibit CYP3A and P-gp by binding directly to the protein: in the CYP3A, Pchs bind to the catalytic site; meanwhile for P-gp, they bind to the cytosolic site (Figure 1).[27-29,35,39-42]

The inhibition mechanism has been reported mainly in flavonoids, which interact directly through the binding of hydroxyls located on carbons C7, C5, and C4 to the heme group of the catalytic site of CYP3A.[28,40-42] These bonds can be competitive and/or non-competitive. Catechin and piperine, for example, bind to CYP3A non-competitively,[28,43,44] while the Pchs of grapefruit, such as bergamottin and its isomers, bind competitively of cytochrome with a Ki equal to that of ketoconazole, a drug considered as a strong inhibitor of CYP3A.[27,41,43,45] The mechanism of inhibition of P-gp is reportedly similar to that of cytochrome, in which the hydroxyls of the flavonoids located in the carbons C5 and C7 bind to the binding site that carries out the transport activity.[46,47]

The timely identification of interactions between medicinal herbs and food components with the same affinity as certain drugs to bind to CYP3A and/or P-gp would greatly help to avoid possible therapeutic failures or adverse reactions produced by changes in drug concentrations.

Based on the above, it can be summarized that Pchs can modify the therapeutic effect of a number of drugs by affecting the expression and activity of the proteins that metabolize and transport them. For example, some drugs produce their therapeutic effect without being metabolized by CYP3A, as is the case with midazolam, because when it is metabolized by CYP3A, inactive metabolites are generated,[31,48-50] while others, such as carbamazepine, need to be metabolized by CYP3A to generate the active metabolites (10,11 epoxi-carbamazepine) that carry out the therapeutic effect. On the other hand, hyperforin activates the expression of cyp3a and abcb1, resulting in increased therapeutic effect of pro-drugs. Unlike Pchs, as galangin and capsaicin, which cause the repression of these genes, producing a decrease in the drugs efficacy.[11,31]

Phytochemical Sources and Pharmacological Effects

Pchs are substances naturally present in vegetables, fruits and herbs. Over time, they have been incorporated into various food supplements as adjuvants to prevent numerous diseases, especially degenerative ones. Various health benefits has been attributed to Pchs, and this is a reason which they are widely used as everyday products (Table 1).

Table 1.

Classification and pharmacological effect of phytocomponents present in vegetables, fruits and herbs.

Classification. Subclassification, presence and pharmacological activities
PHENOLIC COMPOUNDS[98-102]Hidroxibenzoic acids. Present in raspberries, strawberries, cranberry, cinnamon, cloves, mushrooms, fermented dairy products. Pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antiproliferative, antiangiogenic, keratolytic, platelet aggregation moderate antibacterial, antiviral, antifungal, antiprotozoal, nematicidalHidroxicinamic acids. Present in chokeberry, cranberry, blueberry, bilberry, tomato, orange, corn, grapes, beans, potatoes. Pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antiproliferative, antiangiogenic, keratolytic, platelet aggregation moderate antibacterial, antiviral, antifungal, antiprotozoal, nematicidal
STILBENES[51,64,79,102-105]Resveratrol. Present in blueberries (Vaccinium macrocarpon), (Polygonum cuspidatum), Red grape skin and seeds of (Vitis vinifera), blackberries, peanuts and red wine. Pharmacological activities. Protecting from oxidative stress, cardioprotective, diabetes, and neurodegenerative diseases, cancer prevention, a cholesterol-lowering effect
TANNINS[106-113]Catechin: Present in green tea (Camellia sinensis), Grapeseed oil (Vitis vinífera), Pomegranate (Punica granatum), Cacao (Theobroma cacao), Star fruit (Averrhoa carambola). Pharmacological activities. Antioxidant, antimicrobial, antifungal, antiviral, anti-inflammatory, antiallergenic, and anticancer.Epigallocatechin: Present in green tea (C sinensis), Grape (Vitis vinífera) skin and seeds, Pomegranate (Punica Granatum), Cacao (T cacao), Star fruit (A carambola), and high concentration in blueberries (Vaccinium macrocarpon), hazelnuts, pecans nut, apple, peach, mango, pinto beans, red wine and cinnamon. Pharmacological activities. Antimicrobial, antibacterial. Antioxidative, anti-inflammatory, and antitumor agent
FLAVONOIDSFlavonols[41,99,111,114-126]Quercetin: Pomegranate (P granatum), Jamaica flower (Hibiscus sabdariffa), Moringa (Moringa oleífera), Fabaceae (Millettia aboensis), Ginger (Alpinia galanga), Onion (Allium cepa), Cacao (T cacao), Thyme (Thymus saturoides), Guava (Psidium guajava), Valerian (Valeriana officinalis), Fennel (Foeniculum vulgare). Pharmacological activities. Anticancer, antiviral, antiprotozoal, antimicrobial, treatment of; allergic, inflammatory disorders, eye, cardiovascular diseases, and arthritisMorin: Present in guava (P guajava). Pharmacological activities. Anti-inflammatory, antioxidant, anticancer and chemoprotective.Rutin: Present in onion (A cepa) and (Allium obliquum). Valerian (V officinalis), Fennel (F vulgare). Pharmacological activities. It has a role as a metabolite and an antioxidant, anti-diabetic, and anticancerKaemppherol: Present in green Tea, Delphinium, Broccoli, Witch Hazel (Hamamelis virginiana), Grapefruit, Grape, Brussels Sprouts, Apples. Pharmacological activities. Attenuate oxidative stress, anti-inflammatory, antimicrobial, cardioprotector and neuroprotective effects.Myricetin: Present in Jamaica flower (H sabdariffa), strawberry (Fragaria spp.), peepal (Ficus religious), spinach (Spinaceae oleraceae), cauliflower (Brassica oleraceae). Other: Red wine, citics, curly kale, leeks, broccoli, blueberries, cranberry juices. Pharmacological activities. Anti-oxidant, anticancer, antidiabetic, anti-inflammatory, analgesic, antitumor, hepatoprotective and antidiabeticFlavones[111,114,117,120,122,127-134]Apigenine: Present in Carambola (A carambola), Cacao (T cacao), Pomegranate (P granatum), Thyme (T saturoides), Chamomile (Matricaria chamomilla), Doradilla (Anastatica hierochuntia), Onion (A cepa). Other: Parsley, celery, oranges, maize, rice, tea, wheat sprouts, some grasses. Pharmacological activities. Antioxidant, anti-inflammatory, antitoxicant, anticancer, ant-genotoxic, anti-allergic, neuroprotective, cardioprotective, and antimicrobialDiosmetin: Present in Citrus species and other plants (Anastatica hirerochuntica). Pharmacological activities. Phlebotropic, venoprotective, oestrogenic, anticancer, anti-inflammatory, antioxidant, and antimicrobial effects.Chrysin: Present in Blue passion flower (Passiflora caerulea), honey and/or propolis and mushrooms. Diosmetin: Citrus species and other plants (A hirerochuntica). Pharmacological activities. Antispasmodic, sedative, antioxidant, anti-inflammatory, anticancer, and antiviral activitiesGalangin: Present in Parsley (Alpinia officinarum), (Helichrysum aureonitens). Other: Honey, propolis, apple. Pharmacological activities. Anti-mutagenic, anti-clastogenic, anti-oxidative, antimicrobial, anticancer, anti-inflamatory, radical scavenging, metabolic enzyme modulating and anticancer activityLuteolin: Present in Cacao (T cacao), Pomegranate (P granatum), A. hirerochuntica, (Apium graveolens), Parsley (Petroselinum crispum), Broccoli (Brassica oleracea), (T saturoides) thyme, onion (A cepa) (A cepa) leaves, carrots, peppers, cabbages, apple skins, and chrysanthemum flowers are luteolin rich. Pharmacological activities. Anti-inflammation, antiallergy and anticancer, estrogenic and anti-estrogenic activity; anti or pro-oxidantBergamottin (5-geranoxypsoralen): Present in Grapefruit (Citrus paradise), Peel and pulp of orange (C sinensis), Lemon (Citrus aurantifolia), pulp of pomelos. Pharmacological activities. Antioxidative, anti-inflammatory, and anticancerFlavanones or dihydroflavones[2,28,135-140]Naringenin: Present in Grapefruit (C paradise), orange (C sinensis), lemon (C aurantifolia). Pharmacological activities. Anti-inflammatory, anti-cancer, bone health, metabolic syndrome, oxidative stress, genetic damage and central nervous system (CNS) diseases.Hesperetin: Present in Tangerine (Pericarpium citri), Honeybush (Cyclopia subternata). Other sources: Tomatoes, aromatic plants such as mint. Pharmacological activities. Antioxidant and anticancer activity, lipid-lowering, treatment of hemorrhoids and prevention of postoperative thromboembolism, reduction of blood pressure and body fatIsoflavones[65,141]Biochanin: Present in Oregano (Origanum vulgare), Haba (Vicia faba), zallouh or Lebanese viagra (Ferula hermonis), red clover, cabbage, alfalfa. Pharmacological activities. Anti-inflammatory, estrogen-like (estrogenic and/or antiestrogenic activity), treatment: Menopause symptoms, glucose, lipids, cancer, osteoporosis. Cardioprotective and neuroprotective
DIFERULOYLMETHANES[46,56,84,142-144]Curcumin: Present in several species of Zingiberaceae p/e: (Curcuma aromatic), (Curcuma longa), (Curcuma cedoaria), (Curcuma wenyujin), (Curcuma kwangsiensis). Pharmacological activities. Anticancer (chemopreventative and Chemotherapeutic), antioxidant, anti-inflammatory, cardioprotective, antimicrobial, neuroprotective. Inhibits scarring, cataract, and gallstone formation. Prevents liver injury, kidney toxicity, diabetes, multiple sclerosis, Alzheimer’s, HIV disease, septic shock, lung fibrosis, arthritis, and inflammatory bowel diseaseFurocoumarin: Present in Citrus-peel oils and a few other essential oils, for example: Angelica (Angelica archangelica) root and rue (Ruta graveolens). Pharmacological activities. Antioxidative, anti-inflammatory, anticancer and bone health
ANTHOCYANIDINS[101,145-151]Delphinidin: It is found in many brightly colored fruits, vegetables. Pharmacological activities. Antioxidant, antimutagenics, anti-inflammatory and antiangiogenicCyanidin: Present in Apples red flesh (Malus domestica), apple white flesh (Malus spp) and berries (vaccinium corymbosum L) in particular, ed-skinned, hawthorn, bilberries, cranberries, chokeberries. Pharmacological activities. Attributable antioxidant effectPetunidin: It is found in Plant Petunia (Petunia axillaris), blueberries, muscadine (Vitis rotundifolia) is the major source. Other sources: Blueberry (Vaccinium macrocarpon), Jamaica flower (H sabdariffa), Guava (P granatum), Cacao (T cacao), Grape (Vitis vinífera), Raspberry (Rubus idaeus), Cherry (Prunus ceresus), Blackberry (Rubus ulmifolius). Pharmacological activities. Antioxidant, reduces the risk of heart attack
HYPERFORIN[30,75,152-154]It is found in St. John's wort (Hypericum perforatum, Hypericum elodes, Hypericum calycinum). Pharmacological activities. Antidepressants, antibiotic activity against gram-positive bacteria, antitumoral, in addition to the neuronal uptake of serotonin, norepinephrine, dopamine
PROTOALKALOIDS [11,44,49,132,155,156]
Capsaicin or chili pepper (Capsicum): Which can be found in several species of chili (Capsicum). Pharmacological activities. Analgesic properties
ALKALOIDS[157-161]Berberine: Present in Berberis species, Goldenseal (Hydrastis canadensis), Coptidis rhizoma (Rhizomes of Coptis chinensis), Phellodendron chinense Schneid. (Family Rutaceae), genus Mahonia. Pharmacological activities. Berberine and its metabolites such as berberrubine, thalifendine, demethyleneberberine and jatrorrhizine were antimicrobial, anti-diabetic, anti-cancer activities
TERPENES[162-167]Bilobalide contained in Ginkgo biloba: Present in Ginkgo biloba ginkgo tree. Pharmacological activities. Cardioprotective and neuroprotection effect, anticancer activity, in addition, also have toxic effects genotoxicity and carcinogenicityBaicalin present in (Scutellaria radix), from which it is obtained from the dried roots of (S. baicalensis) Georgi and other Scutellaria species, including (S. lateriflora) and S. galericulata. Pharmacological activities. Antitumor, antimicrobial, and antioxidantGinseng (Panax ginseng): Present in several species ginsenosides: (P ginseng) Korean ginseng, (Panax notoginseng) Chinese ginseng, (Panax japonicum) Japan ginseng, and (Panax quinquefolius) American ginseng. Pharmacological activities. Antioxidation, anti-inflammatory, vasorelaxation, antiallergic, antidiabetic, and anticancer, beneficial effects on cardiac and vascularSophora flavescens or Ku Shen: Present in root of Radix (Sophorae flavescentis) Kushen. Pharmacological activities. Antitumor, antimicrobial, antipyretic, antinociceptive, and anti-inflammatoryBunge (Salvia miltiorrhiza): Present in roots of (S miltiorrhiza). Pharmacological activities. Analgesic, anti-cancer, anticoagulant, anti-thrombolitic, anti-allergic, antibacterial, treatment of gastrointestinal hemorrhage, osteoporosis, skin diseases, pyretic stranguria and diuretic agent

The sources were revised as a complement in.

A recent intervention study by Fraga et al., evaluated the metabolism of citrus flavanone and the effect of orange juice on cardiometabolic biomarkers. The authors reported a significant reduction in body fat and blood pressure, suggesting that the consumption of these substances is a good cardioprotective strategy.

Pchs can also have an “anti-diabetic” effect by reducing the absorption of carbohydrates in the small intestine, suppressing tissue gluconeogenesis, increasing tissue glucose uptake, protecting pancreatic beta cells, and increasing insulin secretion. An in vivo study showed that oral administration of rutin-loaded nanophytosomes for 4 weeks was more effective than free rutin in controlling hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats. This “antidiabetic” effect is also evident in the management of blood glucose.

It should be noted that the beneficial health effects attributed to various Pchs have not yet been fully demonstrated, since there is very little scientific evidence on the pharmacological effect of Pchs. Most of the existing evidence is based on the personal experience of the people who consume them (Table 1).

It is important to consider that consuming Pchs from herbs, fruits, and/or vegetables is not always as safe as it seems. It is generally assumed that “everything natural” is beneficial; however, this is not always true, since it depends on many factors such as dose, characteristics of the population, time of consumption, etc.

Drug interactions involving cytochrome CYP3A enzymes and P-gp transporter are mediated through genes activation/repression or protein inhibition. The therapeutic importance of these mechanisms can be observed in clinical practice when drugs that are metabolized and/or transported by CYP3A and P-gp are co-administered with Pchs, which produces an alteration of the bioavailability of the drug and/or the elimination of its compounds.

One of the most important pharmacokinetic parameters related to drug metabolism is the area under the curve (AUC), which involves: the relationship between maximum concentration (Cmax), maximum time (Tmax), time in which the drug reaches its maximum concentration, and clearance (Cl), the most important parameters used to evaluate the absorption and bioavailability of drugs.

Different substances found in plants, mainly flavonoids or alkaloids, can change the expression of the cyp3a and abcb1 genes and activity of CYP3A cytochrome and P-glycoprotein.

Tables 2 and 3 show the results of preclinical and clinical studies that demonstrated a decrease in the AUC of different drugs. This interaction is highly relevant because it can result in ineffective treatments.

Table 2.

Decrease in drug concentrations by modulation Cyp3A/CYP3A by phytochemicals.

Structure Pch	Pch (dose of administration)	Drug (dose of administration)	AUC drug-Pch*	Effect of inhibition
	INHIBITION IN PRECLINICAL STUDIES IN RATS
	FLAVONOLS
	Quercetin (50 mg/kg)	Cyclosporine (CSP) (1.25 mg/kg)	AUC CSP alone= 65.5 ± 25.8 μg/mL/min AUC CSP+quercetina= 37.2 ± 2.2 μg/mL/min	Quercetin decreases (43%) the CSP plasma concentration. Cmax decreased 26
	Rutin (110 mg/kg)	Cyclosporine (CSP) (1.25 mg/kg)	AUC CSP+rutin = 28 ± 11.1 μg/min/mL	Rutin decreases (57%) the CSP plasma concentration. Cmax decreased 26
	FLAVONES
	Galangin (8 mg/kg/day)	Midazolam (MDZ) (5 mg/kg)	AUC MDZ alone= 6454 ± 134 μg/L/hAUC MDZ+Galangin= 1558.15 μg/L/h	Galangin decreases (75%) the MDZ plasma concentration. Tmax and Cmax increase. **The mRNA expression of Cyp3A was repressed 31
	STILBENES
	Resveratrol (20 mg/kg)	Saquinavir (SQV) (30 mg/kg)	AUC SQV alone= 258 ± 12 ng/mL/hAUC SQV+RESV= 177.92 ± 90 ng/mL/h	Resveratrol decreases (31%) the SQV concentration. Cmax increases and Tmax decreases 64
	Resveratrol contents in grape seed extract (80 mg/kg)	Midazolam (MDZ) (20 mg/kg)	AUC MDZ alone= 3.09 ± .79 μg/mL/hAUC MDZ+GSE= 2.37 ± .55 μg/mL/h	It decreases (23%) the MDZ concentration. Cmax decrease, Tmax and clearance increase 48
	DIFERULOYMETHANES
	Curcumin (200 mg/kg)	Buspirone (BUS) (10 mg/kg)	AUC BUS alone= 224 μg/mL/minAUC BUS+CUR= 208 μg/mL/min	Curcumin decreases (7.5%) the BUS plasma concentration. Clearance increases 170
	Curcumin (100 mg/kg)	Everolimus (EVL) (.5 mg/kg)	AUC EVL alone= 1637.7 ± 3 ng/mL/minAUC EVL+cucumin= 466 ± 33 ng/mL/min	Curcumin decrease (72%) the EVL concentration. Cmax decreased 56
	ISOFLAVONES: FLAVANS
	Biochanin A (100 mg/kg)	Tamoxifen (TMF) (10 mg/kg)	AUC TMF alone= 1572.3 ± 90 ng/mL/hAUC TMF+Biochanin= 1065.94 ± 13 ng/mL/h	Biochanin decreases (32%) the TMF plasma concentration. Cmax and Tmax decreased 25
	Biochanin (100 mg/kg)	4-hydroxytamoxifen (10 mg/kg of TMF)	AUC TMF alone= 177.3 ± 90 ng/mL/hAUC TMF+Biochanin A= 107.8 ± 13 ng/mL/h	Biochanin decreases (40%) the 4-TMF plasma concentration. Cmax and Tmax decreased 25
PROTOALKALOIDS
	Capsaicin (30 mg/kg	Midazolam (MDZ) (10 mg/kg)	AUC MDZ alone = 3418.6 ± 26 μg/L/hAUC MDZ+Capsaicin= 2683.46 ± 151 μg/L/h	Capsaicin decreases (21.5%) the MDZ plasma concentration. Cmax and Tmax decreased and clearance increase 49
TERPENES
	Bilobalide and ginkgolide Contained in 100 mg/kg of ginkgo extract	Theophylline (TPL, 10 mg/kg)	AUC TPL alone= 148.3 ± 8.7 μg g/mL/hAUC TPL+ginkgo= 92.2 ± 2 μg/mL/h	Ginkgo decreases (37%) the TPL plasma concentration 67
INHIBITION IN CLINICAL STUDIES IN HEALTHY VOLUNTEERS
FLAVANONES
	Bergamottin contents in 600 mL of grapefruit juice (GFJ)	Celiprolol (CPL) (100 mg)	AUC CPL alone= 814 ± 21 ng/mL/hAUC CPL+(GFJ)= 200 ± 125 ng/mL/h	Bergamottin decreases (75%) the CPL plasma concentration. Cmax decreases and Tmax increases 59
TANNINS
	Epigallocatechin contents in commercial green tea (700 mL)	Nadolol (NDL) (30 mg)	AUC NDL alone = 708.9 ± 56 ng/mL/hAUC NDL+Green tea= 106.6 ± 67 ng/mL/h	Epigallocatechin decreases (85%) the NDL plasma concentration. Cmax and Tmax decreased and clearance increase 60
EFECT IN PROTEIN ACTIVITY IN PRECLINICAL STUDIES (RAT)
FLAVONOIDS AND TERPENES
	Sophora extract (.316 g/kg/day)	Indinavir (IDN) (40 mg/kg)	AUC IND alone= 16.07 ± .99 μg/mL/h AUC IND+Sophora= 7.23 ± .83 μg/mL/h	Sophora extract decreases (55%) the IND plasma concentration. Cmax decreases and Tmax and clearance increases.**The expression of CYP3A was increased at nivel mRNA and protein 8
EFFECT IN PROTEIN ACTIVITY IN CLINICAL STUDIES IN HUMANS IN HEALTHY VOLUNTEERS
Phenolic compounds
	Hyperforin (8 mg) content in tablet with 900 mg of SJW	Digoxin (DGN) (.25 mg)	AUC DGN alone= 7.8 ± 1.6 ng/mL/hAUC DGN+SJW= 6.0 ± 1.3 ng/mL/h	Hyperforin decreases (23%) the plasma DGN concentration. Cmax and Tmax decreases 58
	Hyperforin (.88 mg) contents in 60 mg of SJW	Alprazolam (ALP) (1 mg)	AUC ALP alone = 149 μg/L/hAUC ALP+SJW = 14.4 μg/L/h	Hyperforin decreases (90%) the ALP plasma concentration. Cmax and Tmax 171
	Hyperforin contents in tablet with 300 mg of SJW	Alprazolam (ALP) (2 mg)	AUC ALP alone= 522 ng/mL/hAUC ALP+SJW = 254 ng/mL/h	It decreases (51%) the ALP plasma concentration. Cmax decreases and Tmax increases 62
	Hyperforin (3% to 6%) contents tablet with 900 mg of SJW.	R-Verapamil (VPM) (120 mg/L)	AUC VPM alone= 2406 ± 17 ng/mL/minAUC VPM+SJW= 420 ± 24 ng/mL/min	Hyperforin decreases (82.5%) the plasma concentration of verapamil when co-administered orally. Cmax and Tmax decreases. 172
	Hyperforin (3% to 6%) contents tablet with 900 mg of SJW	S-Verapamil (VPM) (120 mg/L)	AUC VPM alone = 413 ± 31 ng/mL/minAUC VPM+SJW = 56 ± 32 ng/mL/min	It decreases (86%) the VPM plasma concentration. Cmax and Tmax decreases 172
	Hyperforin contents in tablet with 900 mg SJW	Quazepam (QZM) (15 mg)	AUC QZM alone = 217 ± 28 ng/mL/hAUC QZM+SJW= 161 ± 25 ng/mL/h	Hyperforin decreases (26%) the QZM plasma concentration. Cmax decreases and Tmax increases 63
	Hyperforin contents in tablet with 600 mg day of SJW. ***Kidney transplant patients	Cyclosporin (CSP) Constant blood concentration in a range of 100-150 μg/L	AUC CSP alone= 3319 ± 36 μg/L/hAUC CSP+SJW= 2832 ± 38 μg/L/h	It decreases (14.7%) the CSP plasma concentration. Cmax decreases 173
	Hyperforin contents in tablet with 900 mg/day of St. John's wort (SJW)***Kidney transplant patients	Cyclosporine (CSP) (80-150 µmg/L) unchanged for at least 2 months	AUC CSP alone= 3473 ng/mL/hAUC CSP+SJW high= 1671 ± 313 ng/mL/h	Hyperforin decreases (52%) the CSP plasma concentration. Cmax and Tmax decreases 174
TERPENES
	Ginsenosides contents in capsules with 500 mg	Midazolam (MDZ) (8 mg)	AUC MDZ alone= 120 ng/mL/hAUC MDZ+Ginseng= 79 ng/mL/h	Ginsenosides decreases (34%) the MDZ plasma concentration. Cmax decreases and clearance increase 50
	Ginsenosides contents in capsules with 500 mg	Fexofenadine (FDN) (120 mg)	AUC FDN alone= 2036 ng/mL/hAUC FDN+Ginseng= 1860 ng/mL/h	Ginsenosides decreases (9%) the FDN plasma concentration. Cmax decreases, Tmax increases and clearance increase 50
	Bilobalide and ginkgolide in tablets with 240 mg of ginkgo leaf (GBE)	Simvastatin (SMV) (40 mg)	AUC SMV alone= 86.44 ± 35 μg/L/hAUC SMV+GBE= 49.55 ± 2 μg/L/h	Bilobalide decreases (43%) the plasma concentration of SMV. Cmax decreases and Tmax increases 61
	Other plants
	Capsules of danshen (DSC). Salvia miltiorhirza with .56 g	Clopidogrel (CLP) (300 mg)	AUC= CLP alone 16.67 ± 3.39 ng/mL/hAUC CLP+DSC=8.28 ± 1.81 ng/mL/h	S miltiorhirza decreases (50%) plasma concentration of CLP. Cmax, Tmax decrease and clearance increase 66

*AUC value of drug administered alone (control) and co-administered with (Pch). ** Article reporting expression of cyp3a genes.

***Kidney transplant patients. All PCH were co-administered orally with drug in both preclinical or clinical studies. The Pch structure were obtained from the database of Sigma-Aldrich.

Table 3.

Decrease in drug concentrations by modulation abcb1/P-PG BY phytochemicals.

Structure Pch	Pch (dose of administration)	Drug (dose of administration)	AUC drug-Pch*	Effect of inhibition
	INHIBITION IN PRECLINICAL STUDIES IN RAT
			FLAVONOLS
	Quercetin (50 mg/kg)	Cyclosporine (CSP) (1.25 mg/kg)	AUC CSP alone= 65.5 ± 25.8 μg/mL/minAUC CSP+quercetina= 37.2 ± 2.2 μg/mL/min	Quercetin decreases (43%) the CSP plasma concentration. Cmax decreased 26
	Rutin (110 mg/kg)	Cyclosporine (CSP) (1.25 mg/kg)	AUC CSP alone= 65.5 ± 25.8  μg/min/mLAUC CSP+rutin= 28 ± 11.1 μg/min/mL	Rutin decreases (57%) the CSP plasma. Cmax decreased 26
			STILBENES
	Resveratrol (RESV) (20 mg/kg)	Saquinavir (SQV) (30 mg/kg)	AUC SQV alone= 258 ± 12 ng/mL/hAUC SQV+RESV= 177.92 ± 90.5 ng/mL/h	Resveratrol decreases (31%) the SQV plasma concentration. Cmax increases, Tmax decreases and clearance increase 64
			DIFERULOYMETHANES
	Curcumin (100 mg/kg)	Everolimus (EVL) (.5 mg/kg)	AUC EVL alone= 1637.7 ± 3 ng/mL/minAUC EVL+curcumin= 466 ± 33 ng/mL/min	Curcumin decreases (72%) EVL the plasma concentration. Cmax decreased 56
			FLAVANS
	Biochanin (100 mg/kg)	Tamoxifen (TMF) (10 mg/kg)	AUC TMF alone= 1572.3 ± 90 ng/mL/hAUC TMF+ Biochanin= 1065.9 ± 2 ng/mL/h	Biochanin decreases (32%) the TMF plasma concentration. Cmax and Tmax decreased 25
	Biochanin (100 mg/kg)	4-hydroxytamoxifen (10 mg/kg TMF)	AUC TMF alone= 177.3 ± 90 ng/mL/hAUC TMF+Biochanin= 107.8 ± 13 ng/mL/h	Biochanin decreases (40%) the 4-TMF plasma concentration. Cmax and Tmax decreased 25
	INHIBITION IN CLINICAL STUDIES IN HUMANS
			FLAVANONES: (bergamottin)
	Bergamottin in 600 mL of grapefruit juice (GFJ)	Celiprolol (CPL) (100 mg)	AUC CPL alone= 814 ± 21 ng/mL/hAUC CPL+GFJ= 200 ± 125 ng/mL/h	Bergamottin decreases (75%) the CPL plasma concentration. Cmax decreased and Tmax increases 59
			TANNINS: (Epigallocatechin)
	Epigallocatechin contents in commercial green tea (700 mL)	Nadolol (NDL) (30 mg)	AUC NDL alone = 708.9 ± 56 ng/mL/hAUC NDL+Green tea= 106.6 ± 67 ng/mL/h	Epigallocatechin decreases (85%) the NDL plasma concentration. Cmax, Tmax decreased, and clearance increases 60
	EFFECT IN PROTEIN ACTIVITY IN PRECLINICAL STUDIES IN RAT
			FLAVONOIDS AND TERPENES
	Sophora extract (.316 g/kg/day)	Indinavir (IND) (40 mg/kg)	AUC IND alone= 16.07 ± .99 μg/mL/hAUC IND+Sophora= 7.23 ± .83 μg/mL/h	Sophora decreases (55%) the IND plasma concentration. Cmax decreases, Tmax and clearance increase. **The expression of P-gp was increased at nivel mRNA and protein 8
	EFFECT IN PROTEIN ACTIVITY IN CLINICAL STUDIES IN HEALTHY VOLUNTEERS
		TERPENES
	Bilobalide and ginkgolide in tablets with 240 mg of ginkgo leaf (GBE)	Simvastatin (SMV) (40 mg)	AUC SMV alone= 86.44 ± 35 μg/L/hAUC SMV+GBE= 49.55 ± 2 μg/L/h	Bilobalide decreases (43%) the SMV plasma concentration. Cmax decreases and Tmax increases 61
			PHENOLIC COMPOUNDS
	Hyperforin present in table with 900 mg of St John’s wort (SJW)	Talinolol (TLOL) (50 mg)	AUC TLOL alone= 834 ± 45 ng/mL/hAUC TLOL+SJW = 564 ± 36 ng/mL/h	Hyperforin decreases (32%) the plasma concentration of TLOL. Cmax decreases and Tmax increases 57

*AUC value of drug administered alone (control) and co-administered with (Pch). **Article reporting expression of abcb1 genes. All PCH were co-administered orally with drug in both preclinical or clinical studies. The Pch structure were obtained from the database of Sigma-Aldrich.

For example, the AUC of everolimus or cyclosporine decreases after consuming different Pchs, reducing the efficacy of the immunosuppressive treatment (Table 2).[26,56]

Decreased plasma concentrations of celiprolol, talinolol, digoxin, and nadolol, either due to activation/repression of cyp3a and abcb1 or inhibition of CYP3A and P-gp an result in cardiac decompensation, atrioventricular block and acute myocardial infarction.[57-60]

There are also reports of a decrease in the systemic concentration of simvastatin, which is used in the treatment of hypercholesterolemia.

A decrease in the plasma concentration of anxiolytics such as midazolam, alprazolam and buspirone can prevent the desired anxiolytic effect to be achieved, causing patients to suffer anxiety episodes, phobias, panic attacks and intense stress. For midazolam, such a decrease may impair the sedative effect.[50,62]

It has also been reported that a decrease in the plasma concentration of quazepam due to the administration of St John’s wort could put epileptic patients at risk by interfering with the control of seizures, which could then increase in number and making difficult to control the disease.

The plasma concentrations of both saquinavir and indinavir decrease in the presence of some Pchs. Treatment failure can be the cause of disease in HIV-positive patients or in those who require antiviral treatment by preventing the viral load to be adequately reduced, thus failing to stop the disease progression.[8,64]

Patients receiving antineoplastic therapy must take special care with the type and amount of Pchs that are consumed, to avoid a possible therapeutic failure. Some studies have found that biochanin A, present in oregano and broad beans, causes a reduction in the systemic concentration of tamoxifen and its metabolite 4-hydroxytamoxifen (Table 1).[25,65]

The plasma concentration of the antiplatelet clopidogrel decreases when co-administered with the flavonoids found in Salvia miltiorrhiza, which could increase the risk of blood thrombosis and cause cerebrovascular disease or coronary heart disease.

The bioavailability of the antihistamine fexofenadine is affected by the consumption of Ginseng,[50,67] which reduces its plasma concentration and increases its Tmax and clearance, diminishing its therapeutic effect (Tables 2 and 3).

The components of Ginkgo biloba affect the bioavailability of theophylline, reducing its blood concentration. It is important to avoid co-administration of these two substances since it could lead to asthmatic attacks, bronchospasms, and lack of ventilation, among other conditions.

Increase in Drug Concentrations by Modulation cyp3a/CYP3A by Phytochemicals

An increase in the AUC of a drug can also be a consequence genes activation/repression cyp3a/abcb1 or inhibition CYP3A/P-gp as shown in Tables 4 and 5.

Table 4.

Increase in drug concentrations by modulation of cyp3a/CYP3A by phytochemicals.

Structure Pch	Pch (dose of administration)	Drug (dose of administration)	AUC drug-Pch*	Effect of inhibition
PRECLINICAL STUDIES IN RAT
FLAVONOLS
	Quercetin (20 mg/kg/day)	Losartan (LSN) (10 mg/kg)	AUC LSN alone= 7.34 ± .75 mg/mL/hAUC LSN+quercetin= 13.9 ± 1,2 mg/mL/h	Quercetin increases (89%) the LSN plasma concentration. Cmax increased and Tmax decreased 74
	Quercetin in 400 mg/kg of Millettia aboensis (EMA)	Simvastatin (SMV) (20 mg/kg)	AUC Dx+vehicle+SMV= 29.5 ± .48 μg/mL/hAUC DX+EMA+SMV= 69.6 ± .6 μg/mL/h	Quercetin increased (135%) the SMV plasma concentration. Increased Tmax and decreases clearance 175
	Myricetin (8 mg/kg)	Losartan (LSN) 9 mg/kg	AUC LSN alone= 283 ± 57 ng/mL/hAUC LSN+myricetin= 456 ± 88 ng/mL/h	Myricetin increases (61%) the LSN plasma concentration. Cmax and Tmax increase 21
	Morin (15 mg/kg)	Diltiazem (DTZ) (7.5 mg/kg)	AUC DTZ alone= 358 ± 56.9 ng/mL/hAUC DTZ+morin= 642 ± 76.6 ng/mL/h	Morin increased (79%) the DTZ plasma concentration. Cmax increase and decreases clearance 77
	Kaempferol (10 mg/kg)	Nifedipine (NFNE) (10 mg/kg)	AUC NFNE alone= 5930 ± 107 μg/mL/minAUC NFNE+Kaempferol = 9234 ± 1569 μg/min/mL	Kaempferol increase (56%) the NFNE plasma concentration when co-administered orally 73
FLAVONOIDS GLYCOSIDES
	Naringin (7.5 mg/kg). In rabbit	Verapamil (VPM) (9 mg/kg)	AUC VPM alone= 18.4 ± 4.2 μg/mL/minAUC VPM+naringin= 28.4 ± 6.3 μg/mL/min	Naringin increased (54%) the VPM plasma concentration. Cmax increase 78
	Naringin (7.5 mg/kg). In rabbit	Norverapamil (NVPM) (9 mg/kg of verapamil)	AUC NVPM alone= 16.6 ± 4.2 μg/mL/minAUC NVPM+naringin= 19.1 ± 6.3 μg/mL/min	Naringin increased (15%) the NVPM plasma concentration. Cmax increase 78
STILBENES
	Resveratrol contents in 2 g/kg of P. cuspidatum (PC)	Carbamazepine (CBZ) (200 mg/kg)	AUC CBZ alone= 13.3 ± 1.4 mg/mL/minAUC CBZ+PC= 30.3 ± 1.7 mg/mL/min	Resveratrol increased (127%) the CBZ plasma concentration and also in brain, liver and kidney. Cmax increase 51
	Resveratrol contents in 2 g/kg of P. cuspidatum (PC)	Carbamazepine 10,11-epoxide (200 mg/kg of CBZ)	AUC CBZ alone = 25.4 ± 2.6 mg/mL/minAUC CBZ+PC = 44.7 ± 3 mg/mL/min	Resveratrol increased (75.9%) the plasma concentration of CBZ-10,11-epoxide and also in brain, liver, and kidney. Cmax increases 51
	Resveratrol (10 mg/kg)	Diltiazem (DTZ)(15 mg/kg)	AUC DTZ alone= 283 ± 65 ng/mL/minAUC DTZ+resveratrol= 439 ± 98 ng/mL/min	It increased (55%) the DTZ plasma concentration. Cmax increase 79
	Resveratrol (200 mg/kg)	Aripiprazole (APZ) (3 mg/kg)	AUC APZ alone= 158 ± 36 μg/L/hAUC APZ+resveratrol= 634 ± 11 μg/L/h	Resveratrol increased (301%) the APZ plasma concentration. Cmax increases and clearance decreases 90
DIFERULOYMETHANES
	Curcumin (60 mg/kg)	Midazolam (MDZ) (20 mg)	AUC MDZ alone= 255 ± 27 ng/mL/hAUC MDZ+Curcumin= 470 ± 88.3 ng/mL/h	Curcumin increased (84%) the MDZ plasma concentration. Cmax increases and clearance decreases twice 84
TANNINS
	Catechin in green tea extract (GTE) (400 mg/kg)	Midazolam (MDZ) (20 mg/kg)	AUC MDZ alone= 3.09 ± .79 μg/mL/hAUC MDZ+GTE= 9.16 ± 2.5 μg/mL/h	Catechin increased (196%) the MDZ plasma concentration. Cmax and Tmax increase and clearance decreases 48
PROTOALKALOIDS
	Capsaicin (3.0 mg/kg)	Cyclosporin (CSP) (50 mg/kg)	AUC CSP alone= 97.7 ± 26 μg/mL/h AUC CSP+capsicin= 140.4 ± 18.9 μg/mL/h	Capsaicin increases (44%) the CSP plasma concentration. Cmax and Tmax increased. Clearance decreases. **The mRNA expression of CYP3A was repressed in the intestine and liver 11
	CLINICAL STUDIES IN HEALTHY VOLUNTEERS
			FLAVONOLS
	Quercetin contents in valerian tablets (1.0 g)	Alprazolam (ALP) (2 mg)	AUC ALP alone= 472.18 ng/mL/hAUC ALP+Valerian= 538 ± 240 ng/mL/h	Quercetin increases (14%) the ALP plasma concentration. Cmax increased 83
			ANTHOCYANINS
	300 mL of juice (BBJ) contained a concentration of 700- 2100 mg/mL of total anthocyanins predominated: Delphinidin 44.5 μg/mL, Cyanidin 22.7 μg/mL, Petunidin 29.5 μg/mL)	Buspirone (BUS) (10 mg)	AUC BUS alone= 3.11 ± 4.52 ng/mL/hAUC BUS+ BBJ= 4.06 ± .59 ng/mL/h	Anthocyanins increased (30%) the BUS plasma concentration of buspirone. Cmax and clearance decreases and Tmax increases 85
FLAVONONES
	Bergamottin (25-100 μM)contained in 250 mL grapefruit juice (GFJ)	Felodipine (FDP) (10 mg tablets)	AUC FDP alone= 36 ± 8 mol/L/hAUC FDP+GFJ = 65 ±11 mol/L/h	Bergamottin increased (80%) the FDP plasma concentration. Cmax decreased 28
	Bergamottin in 300 mL of grapefruit juice (GFJ)	Felodipine (FDP) (10 mg)	AUC FDP alone= 13 ± 1.6 ng/mL/hAUC FDP+GFJ= 25 ± 4.3 ng/mL/h	Bergamottin increased (92.3%) the FDP plasma concentration. Cmax increased and Tmax decreased 176
	Bergamottin in 250 mL of grapefruit juice (GFJ)	Felodipine (FDP) (5 mg)	AUC FDP alone= 20.1 ± 4.4 nmol/L/hAUC FDP+GFJ= 29.8 ± 7.8 nmol/L/h	Bergamottin increased (48%) the FDP plasma concentration. Cmax increased and Tmax decreased 76
	Bergamottin (12 mg)	Felodipine (FDP) (5 mg)	AUC FDP alone= 20.1±4.4 nmol/h/LAUC FDP+Bergamottin= 26.7 ±8.3 mol/h/L	Bergamottin increased (32.8%) the FDP plasma concentration. Cmax increased and Tmax decreased 76
	Bergamottin in 300 mL of grapefruit juice (GFJ)	Dehydrofelodipine (DFDP) (10 mg Felodipine)	AUC DFDP alone= 16.9 ± 2.6 ng/mL/hAUC DFDP+GFJ= 21 ± 4.2 ng/mL/h	Bergamottin increased (24.2%) the DFPD plasma concentration. Cmax increased and Tmax decreased. 176
	Bergamottin in 300 mL of grapefruit juice (GFJ)	Midazolam (MDZ) (6 mg)	AUC MDZ alone= 64.9 ± 7 ng/mL/hAUC MDZ+GFJ= 106.8 ± 12 ng/mL/h	Bergamottin increased (64%) the MDZ plasma concentration. Cmax increased, clearance is reduced 82
	Bergamottin in 600 mL of grapefruit juice (GFJ)	Midazolam (MDZ) 15 μg/kg	AUC MDZ alone= 11.3 ± 6.18 nmol/L/hAUC MDZ+GFJ= 22.9 ± 13.8 nmol/L/h	Bergamottin increased (100%) the MDZ plasma concentration. Cmax increase 59
	Bergamottin in 240 mL of grapefruit juice (GFJ)	Cyclosporine (CSP) (5 mg/kg)	AUC CSP+Orange juice (control)= 11.3 nmol/L/hAUC CSP+GFJ= 15.6 nmol/L/h	Pch increased (38%) the CSP plasma concentration. Cmax increased, clearance is reduced 86
	Bergamottin in 300 mL of grapefruit juice (GFJ)	Triazolam (TZL) (.1875 mg)	AUC TZL alone= 10.0 ± 3.5 ng/mL/hAUC TZL+GFJ= 16.0 ± 4.7 ng/mL/h	It increases (60%) the TZL plasma concentration. Cmax increased, clearance is reduced 81
	Bergamottin (7.3 mg/mL) in 300 mL of grapefruit juice (GFJ)	Buspirone (BUS) (10 mg)	AUC BUS alone= 3.11 ± 4.06 ng/mL/hAUC BUS+GFJ= 6.15 ± .92 ng/mL/h	Bergamottin increased (97%) the BUS plasma concentration. Cmax, Tmax increased and clearance reduction 85
STILBENES
	Resveratrol (500 mg)	Carbamazepine (CBZ) (200 mg/kg)	AUC CBZ alone= 195.6 ± 39 mg/mL/minAUC CBZ+Resveratrol= 288.7 ± 35 mg/mL/min	Resveratrol increased (48%) the CBZ plasma concentration. Cmax increased, Tmax and clearance decreased 80
DIFERULOYMETHANES
	Furanocoumarin in 240 mL of grapefruit juice (GFJ)	Felodipine (FDP) (10 mg)	AUC FDP+Orange juice (control)= 54 nmol/L/hAUC FDP+GFJ= 110 nmol/L/h	Furanocoumarin increased (104%) the FDP plasma concentration. Cmax increased and clearance reduction 46
ALKALOIDS
	Berberine (76.8 mg) in commercial extract Goldenseal	Midazolam (MDZ)	AUC MDZ alone= 107.9 ± 43 ng/mL/hAUC MDZ+Goldenseal= 175.3 ± 74.8 ng/mL/h	The commercial extract containing berberine increased (62%) the MDZ plasma concentration. Cmax increased and clearance reduction 177
PRECLINICALS STUDIES IN RAT
PHENOLIC COMPOUNDS
	Hyperforin in 300 mg/kg of St John’s wort (SJW)	Methotrexate (MTX) (5 mg/kg)	AUC MTX alone= 163 ± 16.5 μg/mL/hAUC MTX+SJW= 429 ± 56.4 μg/mL/h	Hyperforin increased (163%) the MTX plasma concentration. Cmax increased 33
TERPENES
	Baicalein (10 mg/kg)	Tamoxifen (TMF) (10 mg/kg)	AUC TMF alone= 1834 ± 51 ng/mL/hAUC TMF+baicalein= 3468 ± 898 ng/mL/h	Baicalein increased (89%) the plasma concentration of TMF. Cmax increased and clearance reduction 88
	Baicalein (10 mg/kg)	4-Hydroxy-tamoxifen (TMF) (10 mg/kg of TMF)	AUC TMF alone= 284 ± 65 ng/mL/hAUC TMF+baicalein= 359 ± 95 ng/mL/h	Baicalein increased (26.6%) the plasma concentration of 4-hydroxytamoxifen when co-administered baicalein-TMF. Cmax increased 88
	Bilobalide and ginkgolide in tablets with 80 mg/kg/day ginkgo leaf (GLT)	Losartan (LSN) (10 mg/kg)	AUC LSN alone= 6.99 ± 1.05 mg/L/hAUC LSN+GLT= 11.94 ± 1.8 mg/L/h	Bilobalide increased (70%) the LSN plasma concentration. Cmax, Tmax increased and clearance decreased 72

*AUC value of drug administered alone (control) and co-administered with (Pch). ** Article reporting expression of cyp3a genes. All PCH were co-administered orally with drug in both preclinical or clinical studies. The Pch structure were obtained from the database of Sigma-Aldrich.

Table 5.

Increase of drug by modulation of abcb1/P-gp by phytochemical.

Structure Pch	Pch (dose of administration)	Drug (dose of administration)	AUC drug-Pch*	Effect of inhibition
PRECLINICALS STUDIES IN RAT
FLAVONOLS
	Quercetin (15 mg/kg)	Doxorubicin (DXB) (50 mg/kg)	AUC DXB alone= 186 ± 44 ng/mL/hAUC DXB+Quercetin= 439 ± 107 ng/mL/h	Quercetin increase (136%) the DXB plasma concentration. Cmax increased 22
	Quercetin (20 mg/kg/day)	Losartan (LSN) (10 mg/kg)	AUC LSN alone= 7.34 ± .75 mg/mL/hAUC LSN+quercetin= 13.9 ± 1.2 mg/mL/h	Quercetin increases (89%) the LSN plasma concentration. Cmax increased and Tmax decreased 74
	Rutin (40 mg/kg)	Paclitaxel (PCX) (40 mg/kg)	AUC PCX alone= 1544.32 ± 24 ng/mL/hAUC PCX+Rutin= 3193.53 ± 36 ng/mL/h	Rutin increased (106%) PCX plasma concentration. Cmax and Tmax increased 23
	Myricetin (8 mg/kg)	Tamoxifen (TMF) (10 mg/kg)	AUC TMF alone= 1832 ± 34 ng/mL/hAUC TMF+Myricetin= 3195 ± 60 ng/mL/h	Myricetin increased (174%) the TMF plasma concentration. Cmax and Tmax increased 24
	Myricetin (8 mg/kg)	Tamoxifen (TMF) (10 mg/kg of TMF)	AUC TMF alone= 284 ± 51 ng/mL/hAUC 4-TMF+Myricetin= 352 ± 60 ng/mL/h	Myricetin increased (24%) plasma concentration of 4-TMF. Cmax and Tmax increased 24
	Myricetin (10 mg/kg)	Doxorubicin (DXB) (40 mg/kg)	AUC DXB alone= 179 ± 34 ng/mL/hAUC DXB+myricetin= 390 ± 77 ng/mL/h	Myricetin increased (117%) the DXB plasma concentration. Cmax increased 87
	Myricetin (8 mg/kg)	Losartan (LSN) 9 mg/kg	AUC LSN alone= 283 ± 57 ng/mL/minAUC LSN+myricetin= 456 ± 88 ng/mL/min	Myricetin increase (61%) the LSN plasma concentration. Cmax and Tmax increased 21
	Kaempferol (10 mg/kg)	Nifedipine (NFNE) (10 mg/kg)	AUC NFNE alone= 5930 ± 107 μg/mL/minAUC NFNE+Kaempferol= 9234 ± 1569 μg/mL/min	Kaempferol increase (56%) the NFNE plasma concentration 73
FLAVONONES
	Naringenin (100 mg/kg)	Felodipine (FDP) (10 mg/kg)	AUC FDP alone= 2361.7 ± 34 ng/mL/hAUC FDP+naringenin= 6086.4 ± 47 ng/mL/h	Naringenin increase (157%) the FDP plasma concentration. Cmax increased and clearance decreased 70
	Hesperetin (100 mg/kg)	Felodipine (FDP) (10 mg/kg)	AUC FDP alone= 2361.7 ± 20 ng/mL/hAUC FDP+Hesperetin= 4386.3 ± 38 ng/mL/h	Hesperetin increased (86%) the FDP plasma concentration. Cmax increased and clearance decreased 71
FLAVONES
	Apigenin (40 mg/kg)	Paclitaxel (PCX) (40 mg/kg)	AUC PCX alone= 1300 ± 12 ng/mL/hAUC PCX+apigenin= 4391.67 ± 55 ng/mL/h	Apigenin increased (237%) the PCX plasma. Cmax increased and clearance decreased 23
STILBENES
	Resveratrol contents in 2 g/kg of P. cuspidatum (PC)	Carbamazepine (CBZ) (200 mg/kg)	AUC CBZ alone= 13.3 ± 1.4 mg/mL/minAUC CBZ+PC= 30.3 ± 1.7 mg/mL/min	Resveratrol increased (127%) the CBZ plasma concentration and also in brain, liver and kidney. Cmax increased 51
	Resveratrol contents in 2 g/kg of P. cuspidatum) (PC)	Carbamazepine 10,11-epoxide (200 mg/kg of CBZ)	AUC CBZ alone= 25.4 ± 2.6 mg/mL/minAUC CBZ+PC= 44.7 ± 3 mg/mL/min	Resveratrol increased (75.9%) the plasma concentration of CBZ-10,11 and also in brain, liver, and kidney. Cmax increased 51
	Resveratrol (10 mg/kg)	Diltiazem (DTZ) (15 mg/kg)	AUC DTZ alone= 283 ± 65 ng/mL/minAUC DTZ+resveratrol= 439 ± 98 ng/mL/min	Resveratrol increased (55%) the DTZ plasma concentration. Cmax increased 79
DIFERULOYMETHANES
	Curcumin (60 mg/kg)	Midazolam (MDZ) (20 mg/kg)	AUC MDZ alone= 255 ± 27 ng/mL/hAUC MDZ+Curcumin= 470 ± 88.3 ng/mL/h	Curcumin increased (84%) the MDZ plasma concentration. Cmax increased and clearance decreased 84
	Curcumin (60 mg/kg)	Celiprolol (CPL) (30 mg/kg)	AUC CPL alone= 2140.04 ± 187 ng/mL/hAUC CPL+Curcumin= 2347.63 ± 287 ng/mL/h	Curcumin increased (9%) the CPL plasma concentration. Cmax increased and clearance and tmax decreased 84
TANNINS
	Epigallocatechin gallate (EGCG) (10 mg/kg)	Nicardipine (NCP) (12 mg/kg)	AUC NCP alone= 371 ± 67 ng/mL/hAUC NCP+ EGCG= 663 ± 133 ng/mL/h	Epigallocatechin gallate increased (79%) the NCP plasma concentration. Cmax increased 69
PROTOALKALOIDS
	Capsaicin (3.0 mg/kg)	Cyclosporin (CSP) (50 mg/kg)	AUC CSP alone=97.7 ± 26 μg/mL/hAUC CSP+capsaicin= 140.4 ± 18.9 μg/mL h	Capsaicin increases (44%) the CSP plasma concentration. Cmax and Tmax increased, Clearance is decreased. **The mRNA expression of abcb1 was repressed in the intestine and liver 11
TERPENES
	Ginseng extract (KRG) (100 mg/kg)	Paclitaxel (PCX) (25 mg/kg)	AUC PCX alone= 50.9 ± 12.6 μg/mL/minAUC PCX+KRG= 80.6 ± 14 μg/mL/min	Ginseng increased (57%) the PCX plasma concentration. Cmax, Tmax increased and clearance decreases 89

*AUC value of drug administered alone (control) and co-administered with (Pch). ** Article reporting expression of abcb1 genes. All Pch were co-administered orally with drug in both preclinical or clinical studies. The Pch figures were obtained from the database of Sigma-Aldrich.

Concomitant use of Pchs and medications that are CYP3A substrates may expose the patient to drug interactions and severe side effects, thereby affecting treatment adherence, safety and clinical outcome.

Cardiovascular drugs such as verapamil, norverapamil, losartan, diltiazem, felodipine, nicardipine, dihydrofelodipine and nifedipine increase their plasma concentration when combined with some Pchs, which can lead to severe arterial hypotension, bradycardia, and high toxicity, among others.[21,28,31,46,57,69-79]

An increase in the plasma concentration of anticonvulsants such as triazolam and carbamazepine can produce ataxia, hypotonia, hypotension, respiratory depression, coma, arrhythmia, hemodynamic instability, and death. Carbamazepine, an antiepileptic drug with a narrow therapeutic window, is metabolized to carbamazepine-10,11-epoxide, active metabolite generated by CYP3A. Resveratrol markedly increased the systemic exposure and brain concentration of carbamazepine and its metabolite by inhibiting the CYP3A and P-gp activities. Co-administration of resveratrol with carbamazepine increase the concentration of the drug and its active metabolite in plasma, brain, liver and kidney.[51,80,81]

An unplanned increase in the plasma concentration of the anxiolytics midazolam, alprazolam and buspirone could cause serious problems: increased respiratory rate, lightheadedness, confusion, depression of superficial reflexes, slightly decreased alertness, ataxia, slurred speech, postural instability and even death.[48,59,82-85]

An increase in the plasma concentration of immunosuppressants such as cyclosporine could produce toxicity in kidneys and brain.[11,86]

For some antineoplastic drugs such as methotrexate, doxorubicin, paclitaxel and tamoxifen an increase in their plasma concentrations can cause hematological or myeloid alterations (toxicity) associated with fever, infections, septicemia, septic shock, hemorrhages, tissue hypoxia or death.[22-24,33,87-89]

An increase in the concentration of the antidepressant aripiprazole can produce mild side effects such as blurred vision, fatigue, headache, insomnia, tremors, but also serious side effects such as suicidal tendencies, cardiovascular disorders (hypotension, venous thromboembolism), seizures, neuroleptic malignant syndrome, among others (Tables 4 and 5).

Some terpenes presents in the extract of S. flavescens produces a transcriptional activation of cyp3A and abcb1 genes, meanwhile, capsaicin compounds exhibit cyp3A/abcb1 repression (Table 6).

Table 6.

Phytochemicals That Act in the Same Interaction Of CYP3A and P-gp, Mechanisms That Modify the Concentration of Drugs.

Pch	Effect interaction on CYP3A	Effect interaction on P-gp	Efect on Drug
INHIBITION IN CLINICAL STUDIES IN HUMAN
Bergamottin	Inhibition evaluated with enzymatic activity. Midazolam was used as a specific substrate.	Inhibition transport was assessed celiprolol as a probe substrates.	Midazolam increase (100%)Celiprolol decrease (75%) 59
INHIBITION IN PRECLINICAL STUDIES IN RATS
Quercetin	Inhibition of enzymatic activity produced reduces bioavailability. Ketoconazole was a control of CYP3A inhibition.	Inhibition of transport was assessed with rhodamine 123 in cell cultures which showed a decrease in rhodamine due to quercetin.	Cyclosporine decrease (43%) 26
Quercetin	Inhibition. Enzymatic activity.Quercetin inhibited the CYP IC50% = 14.8 µMol.	Inhibition. Transport evaluated with rhodamine 123 in cell cultures.	Doxorubicin increase (136%) 22
Rutin	Inhibition of enzymatic activity produced reduces bioavailability. Ketoconazole was used as control of CYP3A inhibition.	Inhibition of transport was assessed with rhodamine 123 in cell cultures which showed a decrease in rhodamine due to quercetin	Cyclosporine decrease (57%) 26
Myricetin	Inhibition enzymatic activity. Myricetin inhibited the CYP IC50% = 7.81 µMol.	Transport inhibition was observed by rhodamine 123 accumulation in MCF-7/ADR cells.	Losartan increase (61%) 21
Myricetin	7.8 µM of myricetin was enough to inhibit the 50% the enzymatic activity CYP3A4	Inhibition transport was evaluated with rhodamine 123 in MCF-7/ADR cell cultures.	Doxorubicina increase (117%) 87
Resveratrol	Inhibition evaluated with enzymatic activity. Ketoconazole was control of CYP3A inhibition.	The inhibition of Saquinavir transport was shown using verapamil as a control.	Saquinavir decrease (31%) 64
Resveratrol	Inhibition. Evaluated with enzymatic activity. Ketoconazole inhibition control.	The inhibition of Carbamazepine transport was shown using verapamil as a control.	Carbamazepine increase (127%) 51
Curcuma	Inhibition evaluated with enzymatic activity. Midazolam was used as a specific substrate.	Inhibition transport was assessed celiprolol as a probe substrates.	Midazolam increase (84%)Celiprolol increase (9%) 84
Curcuma	Inhibition evaluated with enzymatic activity. Ketoconazole as an inhibition control.	Inhibition transport was observed with accumulation of rhodamine 123 in LS 180 cells.	Everolimus decrease (72%). 56
Capsaicin	Inhibition observed in mRNA and protein CYP3A in liver and intestine. Induction control was dexamethasone, while the inhibition control was ketoconazole.	Inhibition observed in mRNA and protein P-gp in liver and intestine, verapamil was positive control of P-gp inhibitor, 100 mg/mL.	Cyclosporine increase (44%) 11
Baicalein	Inhibition evaluated with enzymatic activity. Baicalein inhibited the CYP IC50% = 9.6 µMol and ketoconazole inhibition IC50% = 0.3 µMol.	Inhibition transport was assessed with rhodamine 123 in MCF-7/ADR cells cultures.	Tamoxifen increases (89%). 88
Flavonoids present in (Sophora flavescens)	Activation mRNA and protein of cyp3a/CYP3A in intestine and liver.	Activation mRNA and protein of abcb1/P-gp in intestine and liver tissues.	Indinavir decrease (55%) 8

On the other hand, quercetin, bergamottin, myricetin, naringenin, resveratrol, curcumin, baicalein and capsaicin exhibit inhibition of CYP3A and P-gp proteins; this inhibition affects the AUC of different drugs (increase/decrease), for example: quercetin and rutin reduce the cyclosporine plasma concentration by inhibiting both CYP3A and P-gp, however, baicalein increases the tamoxifen concentration by inhibiting the same proteins

Pchs are popularly associated with various beneficial effects such as antioxidant, anticancer and antidiabetic activity and/or good health in general. However, the existing evidence shows that the co-administration of Pchs with some drugs should be further studied to avoid interactions that cause an increase or decrease in the systemic concentrations of the drug and impact in the effectiveness and/or safety of the treatment.

The evidence also shows that interactions between drugs and Pchs have their origin in the modulation of genes cyp3a/abcb1 or in the inhibtion of both proteins CYP3A/P-gp.

These interactions influence the bioavailability of different drugs that are co-administered with food, fruits, vegetables, beverages, and/or food supplements containing different Pchs, and can cause an underdose or an overdose of the drug.[3-5] It is well known that phytomolecules are metabolized through various pathways by phase 1 and 2 enzymes and that they can serve as substrates for drug transporters.[91,92] However, further studies are required to evaluate the influence of the various compounds present in the vegetables consumed in the diet, in medicinal herbs, and generally in any food supplement of vegetable origin.

Conclusion

The identification of drugs that interact with Pchs is of great clinical importance. Mainly, for any drug that is a substrate of CYP3A and/or P-gp caution may need to be exercised when prescribing them. This review provides evidence that drug-Pchs interactions may be as important as drug-drug interactions.

A decrease in drug concentration can lead to therapeutic failure, whereas an increase in concentration for some drugs can lead to toxicity. The information gathered in the present review leads to suggest a better understanding of a patient’s diet to make appropriate recommendations for when to take their medication, if drug-food interactions are possible. Additional research is needed to determine the “dose” of the food that provides sufficient concentrations of these compounds to lead to clinically significant interactions.

Limitations of this Literature Review

A limitation was the impossibility to cover all information that has been reported in the literature about the interaction between Pchs and drugs that are substrates of CYP3A and P-gp. This review included data from the last 2 decades. Thus, significant references on this subject may have been omitted.