Next Article in Journal
Inhibitory Effects of Siegesbeckia orientalis Extracts on Advanced Glycation End Product Formation and Key Enzymes Related to Metabolic Syndrome
Previous Article in Journal
Differential Interaction of Antimicrobial Peptides with Lipid Structures Studied by Coarse-Grained Molecular Dynamics Simulations
Article Menu
Issue 10 (October) cover image

Export Article

Molecules 2017, 22(10), 1699; doi:10.3390/molecules22101699

Review
Phytotherapeutics: The Emerging Role of Intestinal and Hepatocellular Transporters in Drug Interactions with Botanical Supplements
Ghulam Murtaza 1, Naveed Ullah 2, Farah Mukhtar 3, Shamyla Nawazish 4, Saiqa Muneer 5 and Mariam 6,*
1
Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
2
Department of Pharmacy, University of Swabi, Swabi 23340, Pakistan
3
Department of Microbiology, Sardar Bahdur Khan Women University, Quetta 87300, Pakistan
4
Department of Environmental Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
5
Department of Pharmacy, University of Lahore, Lahore 54000, Pakistan
6
Department of Biotechnology, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
*
Correspondence:
Received: 12 September 2017 / Accepted: 2 October 2017 / Published: 21 October 2017

Abstract

:
In herbalism, botanical supplements are commonly believed to be safe remedies, however, botanical supplements and dietary ingredients interact with transport and metabolic processes, affecting drug disposition. Although a large number of studies have described that botanical supplements interfere with drug metabolism, the mode of their interaction with drug transport processes is not well described. Such interactions may result in serious undesired effects and changed drug efficacy, therefore, some studies on interaction between botanical supplement ingredients and drug transporters such as P-gp and OATPs are described here, suggesting that the interaction between botanical supplements and the drug transporters is clinically significant.
Keywords:
botanical supplements; metabolism; drug transporters; P-glycoproteins; organic anion transporting polypeptides

1. Introduction

Health improvement and the treatment or prevention of diseases through the use of botanical supplements has been increasingly adopted over recent decades [1]. This trend may be attributed to the general concept that botanicals are nontoxic because of their natural source and an extensive traditional usage history [2]. Besides, the general public has growing knowledge of health and easy access to botanical supplements [3]. Although, botanicals have been proven efficacious, several botanical extracts may also have noxious fractions [2,3]. On concomitant administration with drugs, botanical supplements may modulate drug metabolism or/and interact with transporters, resulting in their interaction with drugs [4]. This may subsequently influence the pharmacokinetic and pharmacodynamic properties of drugs, leading to their changed efficacy and undesired effects [5,6]. The objective of this article is to concisely discuss the interactions of botanicals and food components with transporters, with special emphasis on clinical relevance of such interactions. While a wide array of studies on in vitro mechanistic and clinical evaluation of numerous botanicals is available in literature, limited studies are described here.

2. Oral Absorption of Coadministered Botanical Ingredients and Drugs

The gastrointestinal tract is the site of food digestion and absorption of digestion products. A large number of studies have reported the molecular mechanisms of the absorption of lipids [7], amino acids [8,9] and sugars [10,11]. The portal vein carries the absorbed components to the liver, where hepatocytes take up or allow them pass on into the systemic circulation. The molecular transport systems involved in nutrient uptake into the liver are well documented [12]. Apart from transporters involved in nutrient uptake, the intestine and the liver cells express other transporters that mediate the uptake of xenobiotics, for example flavonoids [13,14,15].
Xenobiotic transporters not only uptake, but also export the compounds from the enterocytes and the hepatocytes [16,17] (Figure 1). The transport function of these transporters is well studied, but their mode of interaction with and transport of botanical products is still unclear due to various reasons, such as the researchers are still unable to efficiently purify and/or detect many botanical supplements in vitro. Besides, the legislative regulation for botanical supplements is not as strict as for drug usage. Botanical supplements are legislatively categorized as medicinal products and dietary supplements in Europe and the United States, respectively [18]. In Europe, the marketing of botanical supplements is permitted on the basis of bibliographic data on their safety and efficacy profiles, while no such data is required in the United States if botanical supplements contain new food constituents.

3. Transporters in the Intestine

The intestinal movement of nutrients and xenobiotics takes place in accordance with the solute transport principle [19]: Facilitated diffusion is the mechanism for solute uptake (transfer from lumen into cytoplasm of epithelial cells) in the apical membrane of enterocytes, while organic anion transporting polypeptides (OATPs), also known as solute carrier organic anion transporters (SLCO), mediate xenobiotic uptake. OATP2B1 transporter, also abbreviated as SLCO2B1, is an important example of such mediators [20]. This transporter-mediated movement takes place along concentration gradient of solute across epithelial membrane. In addition, there are some transporters, known as secondary active transporters that acquire energy from the sodium or proton gradient and mediate substrate movement against concentration gradient across the apical membrane of enterocytes. These transporters can be exemplified by peptide transporter 1 (PEPT1), also termed as SLC15A1 [21,22]. Facilitated diffusion is also involved in export of substances from enterocytes across the basolateral membrane, for example, efflux of d-glucose [23]; however, very limited information on solute carrier transporter (SLC) expression at the basolateral membrane is available in literature. Otherwise, botanical supplements may be effluxed actively by ATP-binding cassette (ABC) transporters present at the basolateral membrane of enterocytes, for instance, ABCC3 (also termed as multidrug resistance-associated protein 3 or MRP3) that could be involved in baicalin transport across the basolateral membrane of enterocytes [24,25].
It is remarkable that the entry of xenobiotics into the body is restricted by the efflux proteins present in the apical membrane of enterocytes. The examples of these efflux proteins that pump out the xenobiotics into gut lumen are ABCB1 [multidrug resistance protein (MDR1) or P-glycoprotein (P-gp)], ABCC2 (MRP2) and ABCG2 [26,27]. This efflux system can actively limit the transfer of drugs and botanical supplements to the systemic circulation, providing protection against noxious substances [28]. Other substrates for apical ABC transporters include the metabolic products of various xenobiotics such as botanical supplements. The metabolic products may be glucuronides [29].

4. Transporters in the Liver

The intestinal membrane acts as a transport-limiting barrier for xenobiotics, i.e., xenobiotics gain access to portal circulation, and thus to liver, after passing the intestinal obstacle. Then the liver acts as a second transport limiting barrier for xenobiotics before getting access to systemic circulation. The fenestrated sinusoidal endothelial cell layer separates the portal blood from the basolateral membrane of hepatocytes, revealing the direct contact of this basolateral membrane with the portal blood plasma [30]. Several transporters including OATP1B1 (SLCO1B1), OATP1B3 (SLCO1B3), OATP2B1, organic cation transporter 1 (OCT1) (SLC22A1), OCT3 (SLC22A3), organic anion transporter 2 (OAT2) (SLC22A7) and OAT7) (SLC22A9) are expressed on the basolateral membrane of hepatocytes [17,31], while hepatocytes are expected to have additional transporters. ABC transporters such as P-gp, ABCG2 and MRP2 expressed at the canalicular membrane mediate the extrusion of xenobiotics and their metabolites from hepatocytes into bile [32]. Bile transports these xenobiotics into the intestine, from where these molecules are carried back to liver via portal blood, constituting entreohepatic recycling [33]. The canalicular membrane not only contains ABC transporters but also expresses some other transporters such as the SLC transporter multidrug and toxin extruder 1 (MATE1) (SLC47A1), showing its probable contribution to xenobiotic extrusion into the canaliculus [34]. Hepatocyte may also push back the xenobiotics and their metabolites into the portal blood plasma. This transport process is facilitated by ABC transporters such as MRP3 and MRP4 (ABCC4) [32].
The liver not only handles the xenobiotics but also synthesizes bile that transports bile salts from the sinusoidal blood plasma into the canaliculi. Sodium taurocholate cotransporting polypeptide (NTCP) (SLC10A1) and OATPs mediate the hepatocellular uptake of bile salts, while the bile salt export pump (BSEP) (ABCB11) mediate the extrusion of bile salts from hepatocytes into the calaiculi [35]. Xenobiotics may interfere with bile salt extrusion from hepatocytes into the canaliculi, leading to the elevated levels of intracellular bile salt that may result in the development of cholestasis [36].

5. Botanical Supplement-Mediated Cellular Uptake and Efflux

In contrast to chemically synthesized compounds, botanical supplements are impure products due to their procurement as extracts containing multiple substances. Moreover, the compositions of botanical products are not consistent due to the use of different extraction methods. In addition, these products may exhibit significant batch-to-batch variation in the quantities of the individual components. Therefore, the in vivo outcomes may not be accurately extrapolated from in vitro results. The known concentrations of botanical supplements have been used to assess their influence on target proteins or gene expression, however cellular level in vivo findings are unavailable. Thus, it is difficult to investigate the interaction between botanical supplements and drugs. Therefore, regardless of interaction between botanical supplements and drugs, only retrospective investigations are being performed at present [2].

6. Selected Botanical Supplements and their Interactions

A wide array of studies on in vitro and in vivo interactions between various botanicals and transporters are available in literature. Herb-drug interactions were reviewed few years ago [37,38], however many recent studies have added new knowledge to this subject and are reviewed here. This article mainly discusses 10 extensively used botanical supplements that exhibit profound pharmacokinetic interactions with concomitantly used drugs. The in vitro studies revealing the influence of these botanical supplements on various transporters are summarized in Table 1. Moreover, Table 2 describes the interactions of these botanical supplements with different concomitantly used drugs.

6.1. Citrus paradise (Grapefruit) Juice

A wide array of studies has reported the interaction of grapefruit juice with drugs. The first study of this kind, conducted in individuals receiving felodipine together with grapefruit juice, documented a significant increase in its AUC with increased heart rate and lowered blood pressure, likely owing to an increase in its bioavailability [72]. Moderate to severe side effects are observed when grapefruit juice interacts with drugs sharing CYP3A4 as their metabolizing enzyme [98,99]. The examples of drugs metabolized by CYP3A4 are β-blockers, antimalarials and calcium channel blockers.
Moreover, at low concentrations, grapefruit juice modulates P-gp activation in vitro, while P-gp are inhibited at high concentrations of this juice, revealing concentration-dependent biphasic transporter modulation by grapefruit juice. In fact, grapefruit juice enhances the transport of vinblastine and talinolol across Caco-2 cells, showing the suppressive role of P-gp [100,101]. Another study conducted on Madin-Darby canine kidney (MDCK)/MDR cell monolayers treated with low concentrations (<5% v/v) of grapefruit juice, showed significant reduction in the basolateral-to-apical transport of vinblastine across cell layers [102]. In addition, grapefruit juice doubled the rat plasma levels of talinolol, showing grapefruit juice-mediated inhibition of P-gp [103], however, grapefruit juice neither influenced plasma levels of digoxin in human, nor affected the gut P-gp-contents [71,104]. On the other hand, contradictory results were observed whereby grapefruit juice induced a significant reduction in the bioavailability of fexofenadine and celiprolol, possibly due to suppression of uptake transporters by grapefruit juice rather than affecting P-gp and CYP3A4 [44,69].
In fact, grapefruit juice-mediated inhibitory effect on OATP1A2 and OATP2B1 has been confirmed in vitro and in vivo for aliskiren, celiprolol, fexofenadine, repaglinide and talinolol [105]. Other OATP substrates are being studied now to assess the relevance of grapefruit juice interactions with other drugs through OATPs.
Naringenin is the most prevalent flavonoid found in grapefruit juice and has strong OATP1A2 inhibition effects. On the other hand, OATP2B1-mediated transport of estrone-3-sulfate is inhibited in vitro by naringen and quercetin which are two main inhibitors of OATP2B1 in grapefruit juice having very low IC50 values (in a micromolar range). Grapefruit juice contains some other flavonoids including kaempferol, hesperidin, naringenin and phloretin, which have strong OATP2B1 inhibition activity [105,106].
So far, P-gp inhibition effect of grapefruit juice ingredients has been described in few publications, while cellular studies have demonstrated the decline in P-gp-mediated efflux of vincristine and saquinavir in the presence of naringenin and bergamottin. In addition, at low concentrations, quercetin and kaempferol modulates P-gp activation in vitro, while P-gp are inhibited at high concentrations, revealing concentration-dependent biphasic transporter modulation by these two flavonoids [107,108]. On the basis of existing clinical studies, in the future “this drug may interact with grapefruit juice” labelling may be required by the FDA for certain drugs such as felodipine, cyclosporine and simvastatin.

6.2. Citrus sinensis (Orange) Juice

Keeping in view the interactions mediated by grapefruit juice, other citrus fruits have also been screened for any potential inhibitory effects on concomitantly administered drugs. In comparison to sweet oranges, bitter oranges have significantly higher potential to suppress CYP3A4. An important reason for this difference is the presence of bergamottin and its metabolite (6′,7′-dihydroxy-bergamottin) in bitter oranges [108]. A study has reported 76% higher value of plasma felodipine concentration when coadministered with bitter orange juice as compared with sweet orange juice [109]. Since sweet orange juice shows no effect on CYP3A4, clinically significant interactions have been exhibited by this juice, mediated through OATPs. Its interactions were found more significant than those for grapefruit juice. The plasma levels of various OATP2B1 substrates such as atenolol and fexofenadine were markedly decreased in healthy volunteers when cotreated with sweet orange juice. In fact, orange juice-mediated inhibition of OATP2B1 is demonstrated by in vitro studies [65,110], the screening of sweet orange juice interactions mediated through OATP are necessary in human.

6.3. Malus pumila (Apple) Juice

To date, the role of CYP3A4 and P-gp in the interactions of apple juice with drugs in human has not been investigated. However, several studies suggest that apple juice interacts significantly with OATP2B1. The coadministration of apple juice and fexofenadine exhibit significant decline in plasma drug concentration, which are more significant than those noted for sweet orange juice and grapefruit juice [44]. A previous study has already demonstrated the inhibitory effect of apple juice (about 250 mL) on OATP2B1, revealing that large volumes or repeated intake of apple juice is not required for OATP2B1. Due to this reason, OATP2B1 expressed in Xenopus laevis oocytes is inhibited by apple juice for longer period of time than that by grapefruit juice [110]. Moreover, the bioavailability of several OATP2B1 substrates such as fexofenadine, atenolol and talinolol was significantly decreased by apple juice in human subjects [111]. It is remarkable that concurrently administered apple juice and grapefruit juices did not affect the bioavailability of OATP2B1 substrates such as pravastatin and pitavastatin [105]. It indicates that their absorption depends on OATP2B1 to an insignificant extent. It can also be justified on the basis of fact that diminished intestinal uptake is moderated by decreased uptake into the liver cells. So far, no study has reported the elucidation of the apple juice compounds that induce OATP inhibition in the intestine, although OATP2B1 is significantly inhibited by phloridzin, a flavonoid present in apple juice [64,65,106]. It is remarkable that the interactions of fruit juices with drugs cannot be anticipated precisely due to variable concentrations of apple juice constituents responsible for OATP inhibition depending on fruit species, harvesting season, extraction and storage conditions.

6.4. Silybum marianum (Milk Thistle)

Upper alimentary canal and liver diseases are traditionally treated by many natural remedies including Silybum marianum, generally known as milk thistle [112]. Milk thistle seeds contain several constituents, which are extracted for further use. The term “silymarin” is generally used for milk thistle seed extract [113]. Silymarin contains silybin (also named as silibinin) as key ingredient, which is a flavonolignans mixture; however, small quantities of chemically unknown constituents are also present in silymarin [114]. Although the clinical effectiveness of silymarin has been reported in several publications, no study evidently describes the clinical efficacy of thistle milk products [115,116]. This scarcity could be attributed to the ambiguous terminologies used for thistle milk products [114]. The intoxications due to ingestion of Amanita phalloides, a lethal fungus, has been effectively treated by silymarin [114,116,117], while a formulation with defined quantities of its constituents is being marketed [117]. The literature study showed no evidence about the accurate mode of silymarin action against Amanita phalloides, but the antioxidant potential, among others, is an important property of this botanical supplement [112,117,118].
Amatoxins (amanitin) and phallotoxins (phalloidin) are the major toxins in Amanita phalloides [117]. These toxins are transported via OATPs in human hepatocytes: OATP1B3 and OATP1B1 mediate the transport of amanitin [119] and phalloidin, respectively [120,121]. Moreover, rat NTCP also mediate the transport of amanitin [119]; however, in this context, the role of human NTCP has not been studied yet. It is remarkable that OATP1B3 is inhibited by silibinin dihemisuccinate, which can thus suppress the transport of amanitin [118,119]. It is concluded that the intoxications due to ingestion of Amanita phalloides is likely cured by silibinin dihemisuccinate via suppression of amanitin uptake into hepatocytes.
In case of failure of standard therapy in curing hepatitis C infection, patients have been successfully treated with high-dose of intravenously administered silibinin dihemisuccinate [122,123,124,125]. Moreover, this regimen helps in treating patients with hepatitis C and human immunodeficiency virus (HIV) coinfections [126]. Hepatitis C patients treated with high-dose silibinin dihemisuccinate have the elevated levels of bilirubin [61]. OATP1B3 and OATP2B1 are competitively inhibited in vitro by silibinin and its Ki values are similar to those observed for plasma levels of silibinin dihemisuccinate. On the other hand, studies have revealed complex interactions between silibinin dihemisuccinate and OATP1B1: silibinin dihemisuccinate suppresses the high-affinity binding site (IC50 = 3.8 μM), while silibinin stimulates the transport by low-affinity binding site at a concentration <10 μM but suppresses at higher concentration [61]. Additionally, bilirubin transport is mediated by OATP1B1 and OATP1B3 [127]. Moreover, MRP2 is inhibited by silibinin dihemisuccinate, which has no interaction with BSEP and NTCP [61].

6.5. Camellia sinensis Leaves (Green Tea)

Green tea is used worldwide. Different dietary supplements and beverages are prepared from green tea extracts. Various in vitro and in vivo studies involving human intestinal and hepatic microsomes have revealed the inhibitory effect of green tea on CYP3A4 [105], resulting in the significantly increased AUC of simvastatin compared with control group [128]. So far, the available studies on the interaction between green tea and CYP3A4 substrates have not reported any clinically profound findings. In a four week study, the daily intake of green tea catechins at a dose having 800 mg epigallocatechin gallate (EGCG), subsequently buspirone bioavailability was increased by 20%, likely due to CYP3A4 inhibition [82]. Moreover, the in vitro and animal studies on green tea catechins show that P-gp is not affected by epicatechin, whereas EGCG, epicatechin gallate (ECG) and epigallocatechin have modulating effect on P-gp, with the highest potency for EGCG and the lowest for epigallocatechin (EGC) [53]. However, so far no study describe the determination of the clinical significance of P-gp substrate inhibition by green tea catechins. Another study described the estrone-3-sulfate uptake inhibition by the green tea catechins EGCG and ECG in the cells expressing OATP1A2, OATP1B1 and OATP2B1 [62]. It is also found in cytotoxicity studies that EGCG is transported by OATO1B3 [15]. Remarkably, the average concentration of EGCG and ECG in the brewed green tea was approximately 400 μM, so that the maximal concentrations were in the low millimolar range [62]. Therefore, an intestinal concentration of EGCG and ECG in the same range of the IC50 values may be achieved by taking a few cups of green tea, and as a result, clinically significant interactions may be observed. In fact, a clinical study showed significant decline in the AUC of nadolol after repeated use of a catechol rich green tea [83]. Future studies may be focused on the interaction of catechins-enriched green tea supplements with OATP1A2 and OATP 2B1.

6.6. Glycine max Merrill (Soybean)

The menopausal women regularly use soy extracts or its pure compounds to compensate harmonic regulations. The major isoflavones in soy are genistein and daidzein, which have low oral bioavailability due to their extensive glucuronidation in the intestine and liver. MRP2 extrudes glucuronides into bile, thus activating bile flow by approximately 15% in isolated perfused rat liver [129]. So far, no data is available on the choleretic effect in humans after oral administration of soy supplements. However, genistein may competitively inhibit MRP2-mediated biliary excretion of glucuronides, and same finding was observed when genistein addition diminished biliary excretion of bilirubin conjugates by 76% in a rat model [129]. Genistein and daidzein, both are known as ABCG2 inhibitors, profoundly inhibited milk secretion of ABCG2 substrate danofloxacin, resulting in about 50% decline in its milk/plasma ratio [42]. The role of genistein as P-gp inducer and OATP1B1 inhibitor has been demonstrated using various cellular models [48,63], in vivo data in this context is not available. However, two studies in human suggested significant drug interactions of soy milk on warfarin deficiency, resulting in reversible subtherapeutic international normalized ratio (INR), enhancing thromboembolic risk [84,130]. Further studies are required to investigate whether soy milk-induced INR decrease is triggered by changes in warfarin transport, its metabolism or both. The coadministration of warfarin with soy supplements needs essential care.

6.7. Hypericum perforatum (St. John’s Wort)

Above discussion outlines the inhibition of transporters by botanical supplements. Besides, the regulation of gene expression is affected by the supplements, for instance, Hypericum perforatum (H. perforatum, St. John’s wort). Placebo-controlled clinical trials have proved that the effectiveness of H. perforatum in depression is comparable to standard therapies [131]. Hypericin is one of the major constituents of H. perforatum; however, H. perforatum contains other constituents, which contribute to the hypericin action [132]. Several in vitro and animal studies have been conducted to explore the mode of action of H. perforatum [133,134]. H. perforatum extracts interact with several drugs, likely due to complex composition of this supplement [135,136]. Hyperforin is the major ingredient that contribute to these interactions as well as activates the nuclear transcription factor pregnane X receptor [137]. Moreover, several CYPs are inhibited by crude extracts of H. perforatum [138]. These two results reveal that the inconstant composition of H. perforatum extracts affects drug disposition that is difficult to be determined in individual formulations.
The studies have reported the extremely low bioavailability of cyclosporine in transplant patients using H. perforatum extracts [139,140,141]. The impact of H. perforatum extract on digoxin bioavailability in both human and rats was investigated at the protein level [45]. This study described the enhanced induction of hepatic rCYP3A2 by 2.5-fold and intestinal P-gp by 3.8-fold in rats supplemented with H. perforatum extract for 14 days [45]. On the other hand, the expression of intestinal rCYP3A2 was enhanced by 2.5-fold and hepatic P-gp was unaffected. Moreover, the increased induction of intestinal CYP3A4 by 1.5-fold and P-gp by 1.4-fold in humans supplemented with H. perforatum extract for 14 consecutive days was also reported [45]. H. perforatum extract intake effects on human-induced hepatic CYP3A4 were evidenced by increased demethylation of erythromycin. In parallel with these changes, the AUC0–7h of digoxin was also reduced. Hence, uptake of a reduced P-gp substrate (for example, cyclosporine) across the apical membrane of enterocytes and an increased metabolism of CYP3A4 substrates by H. perforatum was described, explaining that reduced plasma levels of cyclosporine are likely due to an increased first pass effect. These findings clarify the effects of H. perforatum on the pharmacokinetics and thus the pharmacodynamics of several drugs and indicate the compromised efficacy of oral contraceptives [142,143]. The above study on H. perforatum evidently describes the moderate level botanical supplement-mediated change in expression levels of key enzymes and transporters involved in the first-pass effect, influencing the pharmacokinetics that may lead to therapeutic failure of drugs with severe clinical consequences [144,145]. Therefore, it is critically important that the health-care professionals counsel and educate the patients about the use of botanical supplements.

6.8. Cynara scolymus (Artichoke)

The traditional use of botanical products for human health care started several thousands of years ago [146,147]. People across the world generally use botanical supplements to treat hepatic disorders, including among others hepatitis C [148,149]. The ancient Greeks used Cynara scolymus (C. scolymus; artichoke) leaf extracts, which are useful for choleretic and anticholestatic effects and to reduce lipid contents [150,151]. The induction of choleresis in rats has already been demonstrated [152]. The choleretic effect is also observed in human, as evident from the augmented release of bile into duodenum in humans supplemented with C. scolymus [153]. Cynarin and luteolin are major ingredients of C. scolymus extracts [154]. Cynarin weakly inhibits OATP2B1 [155], and thus is capable of reducing OATP2B1-mediated uptake of drugs by the liver and intestinal cells. However, no evidence is available on whether cynarin is an OATP2B1 substrate. Moreover, the literature study reveals no description of luteolin transporters, although the metabolism of luteolin widely produces glucuronides that may act as ABCG2 substrate [156].

6.9. Resveratrol

Resveratrol is a stilbenoid and belongs to the polyphenol group of natural compounds. Resveratrol can be isolated in low quantities from red grapes, red wine and berries [157]. A large number of preclinical and clinical studies have demonstrated the antiinflammatory, antiobesity, antidiabetic, antiaging, anticancer and neuroprotective role of resveratrol [158]. Resveratrol is extensively metabolized into sulfates and glucuronides in the intestine and liver, resulting in low concentrations of intact resveratrol in blood and tissues. As a result, the bioavailable levels of resveratrol are inadequate to explain its observed pharmacological activities [159,160]. Therefore, since resveratrol is categorized as a dietary supplement, the USA Food and Drug Administration (FDA) has not approved its efficacy as a drug.
The active transport of resveratrol and its conjugates has been demonstrated by many in vitro and animal studies. Whereas the efflux of resveratrol glucuronides occurs through MRP2 and MRP3 [161,162]. Moreover, the kinetics of resveratrol uptake by OATP1B1, OATP1B3 and OATP2B1 is a saturable process. Only OATP1B3 transports resveratrol-3-O-sulfate, while both OATP1B1 and OATP1B3 are involved in resveratrol-3-O-4′-O-disulfate transportation. It is remarkable that none of the three OATPs have affinity with resveratrol-4′-O-sulfate, resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide [16].
The safety profiles of resveratrol have suggested it a safe remedy having no undesired effects on human health if taken alone in a concentration less than 100 mg per day, even for several months. However, higher doses of resveratrol (≥1 g) can produce some undesired effects, such as gastrointestinal problems and hot flashes.
ABC transporters are inhibited in vitro by resveratrol, for instance, resveratrol ameliorates the cytotoxicity of doxorubicin and docetaxel through the suppression of P-gp and downregulation of the ABCB1 gene [163]. Similarly, resveratrol enhances the intestinal absorption of bestatin via downregulation of ABCB1 and ABCC2 gene and their respective mRNA levels [164]. Another study in non-small-cell lung cancer cell lines has revealed resveratrol-mediated inhibition of ABCG2 [165]. However, the evidences for resveratrol-mediated inhibition of ABC transporters and OATPs in patients and the subsequent drug interactions are scarce at best. In addition, same studies may be carried out for resveratrol metabolites. Resveratrol-transporter interaction may be tested only in the intestine, since 8 day treatment of colon cancer patients with resveratrol (1 g/day) achieved high concentrations for resveratrol (674 μM) and its metabolite resveratrol-3-O-sulfate (67 μM) [166]. The concentration of resveratrol-3-O-4′-O-disulfate can be presumed to be equal to resveratrol-3-O-sulfate, since both metabolites are currently identified at the same level in human plasma [167]. Resveratrol-containing supplements must be taken cautiously, since several supplements have more than 250 mg of resveratrol. In fact, the interaction of resveratrol with drugs is supported by many earlier studies. For instance, coadministration of resveratrol (1 g/day) with cytochrome P450 (CYP) substrates to healthy individuals showed the inhibition of CYP2C9, CYP2D6 and CYP3A4, resulting in increased side effects [168]. Actually, resveratrol (500 mg/day as single dose for 10 day) coadministered with diclofenac and carbamazepine to healthy individuals showed significant increases in maximum plasma concentration (Cmax) and area under zero moment curve (AUC) of both drugs. This increase in pharmacokinetic parameters was attributed to the inhibition of CYP2C9 and CYP3A4, respectively.

6.10. Anthocyans

Anthocyans occur in plants as flavonoid pigments that contribute the purple, blue, and red colors of grapes and berries. Anthocyans include both glycodies and aglycones, termed as anthocyanins and anthocyanidins, respectively. Anthocyanin-enriched water extracts and juices are available as dietary supplements to achieve various health benefits. It is remarkable that various dietary supplements contain high concentrations (approximately 200 mg) of anthocyanins per dose. Anthocyanins and anthocyanidins have inhibitory effect on various CYP isozymes in vitro. For instance, delphinidin and pelargonin have CYP3A4 and CYP2C9 inhibitory effects, respectively [169]. In addition, P-gp and ABCG2 are slightly inhibited by berry anthocyanins [170,171]. However, the confirmation of these in vitro effects needs clinical studies, as while midazolam bioavailability was significantly increased on concurrent use with a double dose of cranberry juice in one study, another study could not confirm this finding [172]. One possible reason of this contradictory finding could be the significant variations in the contents of anthocyanins in various fruits. Cranberry juice has no interaction in human with certain drugs such as tizanidine, amoxicillin and flurbiprofen [172]. The probable interaction between cranberry juice and CYP2C9 substrate warfarin is clinically important. In this context, five clinical studies were conducted that revealed no change in the oral bioavailability [172]. However, the supplementation of cranberry juice concentrate to human followed by single high dose of warfarin resulted in increased INR that was correlated with bleeding episodes [173]. Owing to this reason, the label “warfarin may interact with cranberry juice” is required by the FDA. CYP3A4 and CYP3A9 substrates and large quantities of cranberry juice (more than 1 L per day) or its concentrated supplement (approximately 1 g per day) should not be concurrently used for prolonged time periods. In a previous study, the influence of 21 anthocyanins and their six relevant anthocyanidins on OATP1B3 and OATP1B1 expression in human hepatocytes was investigated in vitro [174]. Pelargonin and dolphin reduced OATP1B3 expression, while OATP1B1 expression was enhanced by malvin, malvidin-3-O-galactoside, and cyaniding-3-O-sophoroside, revealing that OATP1B3 and OATP1B1 expression can be altered by different anthocyanins. So far, there is no evidence neither of anthocyanin-mediated altered expression of intestinal OATP1B3 and OATP1B1 nor of clinical interaction of anthocyanins with intestinal OATP1B3 and OATP1B1.

6.11. Other Botanical Supplements

In addition to the botanical supplements described above, drug disposition might be affected by many other botanical supplements and food ingredients including Glycyrrhiza glabra (licorice) [56], Piper nigrum (black papper) [47], Allium sativum (garlic) [51], Ginkgo biloba (ginkgo) [57], Panax ginseng (ginseng) [59], Curcuma longa (turmeric) [54], Cimicifuga racemosa (black cohosh) [66], Echinacea family [175] and Peumus boldo [46]. It is remarkable that Allium sativum, Echinacea, Ginkgo biloba, Glycyrrhiza glabra and Panax ginseng are P-gp inhibitors. In rats, P-gp and ABCG2 are induced by piperine and boldine, isolated by Piper nigrum and Peumus boldo, respectively. Curcumin isolated from Curcuma longa inhibit ABCG2, which, in contrast, is induced by diallyl disulphide found in Allium sativum. In addition, all these plants and their ingredients have OATP inhibition features. The above findings are obtained from in vitro studies. Only a few of these entities have been investigated for their pharmacokinetic assessment, revealing drug interactions with these botanicals, based on the clinical relevant enzyme- or transporter-based interactions. Allium sativum intake resulted in subtherapeutic INR of fluindione due to induction of CYPs [90]. The decline in midazolam AUC was observed on coadministration with Echinaecea purpurea, likely due to induction of CYP3A4 in hepatocytes [91], however Gingko biloba and Panax ginseng inhibited CYP3A4, resulting in increase in AUC of midazolam [94,97]. The ingestion of Piper nigrum leads to increase in AUC of phenytoin [176]; however a mechanistic interpretation for this observation is needed.

7. Conclusions

The pharmacokinetics and pharmacodynamics of drugs coadministered with botanical supplements are significantly altered. This review article discusses the effects of some botanical supplements on drug transporters in the intestinal and hepatic cells, since the bioavailability of orally administered drugs depends on the first pass effect. The increased first pass effect may lead to subtherapeutic effect, while severe consequences may appear if first pass effect is reduced. To tackle these recognized interaction issues, FDA has requested the addition of warning labels in some instances, such as warfarin. Self-medication with botanical supplements may lead to harmful effects or even the therapeutic failure of drugs, thus our knowledge must be enhanced to avoid unpleasant interactions of botanical supplements with drugs, and hence to improve therapeutic effectiveness. Since plant constituents have a close association with enzymes and transporters for disposition of drugs and xenobiotics in human and animals, the understanding of drug disposition can be enhanced through improved understanding of detailed mechanisms involved in the interaction of botanical supplements and food constituents. Thus, it is also necessary to interpret the mode of interaction between botanical supplements and drugs, however, there are several hindrances in these mechanistic investigations, such as the unavailability of pharmacokinetic data of individual active constituents of botanical supplements in humans, variation in the relative contents of botanical supplements between suppliers and between batches, and interindividual variability of the different transporters and metabolizing enzymes.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. De Lima Toccafondo Vieira, M.; Huang, S.M. Botanical-drug interactions: A scientific perspective. Planta Med. 2012, 78, 1400–1415. [Google Scholar] [CrossRef] [PubMed]
  2. Calitz, C.; du Plessis, L.; Gouws, C.; Steyn, D.; Steenekamp, J.; Muller, C.; Hamman, S. Herbal hepatotoxicity: Current status, examples, and challenges. Exp. Opin. Drug Metab. Toxicol. 2015, 11, 1551–1565. [Google Scholar] [CrossRef] [PubMed]
  3. STICKEL, F.; SHOUVAL, D. Hepatotoxicity of herbal and dietary supplements: An update. Arch. Toxicol. 2015, 89, 851–865. [Google Scholar] [CrossRef] [PubMed]
  4. Domitrovic, R.; Potocnjak, I. A comprehensive overview of hepatoprotective natural compounds: Mechanism of action and clinical perspectives. Arch. Toxicol. 2016, 90, 39–79. [Google Scholar] [CrossRef] [PubMed]
  5. Li, Y.; Paxton, J.W. The effects of flavonoids on the ABC transporters: Consequences for thepharmacokinetics of substrate drugs. Exp. Opin. Drug Metab. Toxicol. 2013, 9, 267–285. [Google Scholar] [CrossRef] [PubMed]
  6. Haefeli, W.E.; Carls, A. Drug interactions with phytotherapeutics in oncology. Exp. Opin. Drug Metab. Toxicol. 2014, 10, 359–377. [Google Scholar] [CrossRef] [PubMed]
  7. Hussain, M.M. Intestinal lipid absorption and lipoprotein formation. Curr. Opin. Lipidol. 2014, 25, 200–206. [Google Scholar] [CrossRef] [PubMed]
  8. Palacin, M.; Estevez, R.; Bertran, J.; Zorzano, A. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol. Rev. 1998, 78, 969–1054. [Google Scholar] [PubMed]
  9. Poncet, N.; Taylor, P.M. The role of amino acid transporters in nutrition. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 57–65. [Google Scholar] [CrossRef] [PubMed]
  10. Wright, E.M. Glucose transport families SLC5 and SLC50. Mol. Asp. Med. 2013, 34, 183–196. [Google Scholar] [CrossRef] [PubMed]
  11. Mueckler, M.; Thorens, B. The SLC2 (GLUT) family of membrane transporters. Mol. Asp. Med. 2013, 34, 121–138. [Google Scholar] [CrossRef] [PubMed]
  12. Rui, L. Energy metabolism in the liver. Compr. Physiol. 2014, 4, 177–197. [Google Scholar] [PubMed]
  13. Khan, F.A.; Maalik, A.; Murtaza, G. Inhibitory mechanism against oxidative stress of caffeic acid. J. Food Drug Anal. 2016, 24, 695–702. [Google Scholar] [CrossRef] [PubMed]
  14. Tenore, G.C.; Daglia, M.; Ciampaglia, R.; Novellino, E. Exploring the nutraceutical potential of polyphenols from black, green and white tea infusions—An overview. Curr. Pharm. Biotechnol. 2015, 16, 265–271. [Google Scholar] [CrossRef] [PubMed]
  15. Murtaza, G.; Sajjad, A.; Mehmood, Z.; Shah, S.H.; Siddiqi, A.R. Possible Molecular Targets for Therapeutic Applications of Caffeic Acid Phenethyl Ester in Inflammation and Cancer. J. Food Drug Anal. 2015, 23, 11–18. [Google Scholar] [CrossRef] [PubMed]
  16. Stieger, B.; Mahdi, Z.M.; Jager, W. Intestinal and Hepatocellular Transporters: Therapeutic Effects and Drug Interactions of Herbal Supplements. Annu. Rev. Pharmacol. Toxicol. 2017, 57, 399–416. [Google Scholar] [CrossRef] [PubMed]
  17. Stieger, B.; Meier, P.J. Pharmacogenetics of drug transporters in the enterohepatic circulation. Pharmacogenomics 2017, 12, 611–631. [Google Scholar] [CrossRef] [PubMed]
  18. Seeff, L.B.; Bonkovsky, H.L.; Navarro, V.J.; Wang, G. Herbal products and the liver: A review of adverse effects and mechanisms. Gastroenterology 2015, 148, 517–532. [Google Scholar] [CrossRef] [PubMed]
  19. Kramer, R. Functional principles of solute transport systems: Concepts and perspectives. Biochim. Biophys. Acta 1994, 1185, 1–34. [Google Scholar] [CrossRef]
  20. Kobayashi, D.; Nozawa, T.; Imai, K.; Nezu, J.; Tsuji, A.; Tamai, I. Involvement of human organicanion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J. Pharmacol. Exper. Ther. 2003, 306, 703–708. [Google Scholar] [CrossRef] [PubMed]
  21. Govindarajan, R.; Bakken, A.H.; Hudkins, K.L.; Lai, Y.; Casado, F.J.; Pastor-Anglada, M.; Tse, C.M.; Hayashi, J.; Unadkat, J.D. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am. J. Physiol. 2007, 293, R1809–R1822. [Google Scholar] [CrossRef] [PubMed]
  22. Groneberg, D.A.; Doring, F.; Eynott, P.R.; Fischer, A.; Daniel, H. Intestinal peptide transport: Ex vivo uptake studies and localization of peptide carrier PEPT1. Am. J. Physiol. 2001, 281, G697–G704. [Google Scholar]
  23. Dawson, P.A.; Hubbert, M.L.; Rao, A. Getting them OST from OST: Role of organic solute transporter, OSTα-OSTβ, in bile acid and steroid metabolism. Biochim. Biophys. Acta 2010, 1801, 994–1004. [Google Scholar] [CrossRef] [PubMed]
  24. Kalapos-Kovacs, B.; Magda, B.; Jani, M.; Fekete, Z.; Szabo, P.T.; Antal, I.; Krajcsi, P.; Klebovich, I. Multiple ABC transporters efflux baicalin. Phytother. Res. 2015, 29, 1987–1990. [Google Scholar] [CrossRef] [PubMed]
  25. Van de Wetering, K.; Feddema, W.; Helms, J.B.; Brouwers, J.F.; Borst, P. Targeted metabolomics identifies glucuronides of dietary phytoestrogens as a major class of MRP3 substrates in vivo. Gastroenterology 2009, 137, 1725–1735. [Google Scholar] [CrossRef] [PubMed]
  26. Li, Y.; Lu, J.; Paxton, J.W. The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics. Curr. Drug Metab. 2012, 13, 624–639. [Google Scholar] [CrossRef] [PubMed]
  27. Planas, J.M.; Alfaras, I.; Colom, H.; Juan, M.E. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters. Arch. Biochem. Biophys. 2012, 527, 67–73. [Google Scholar] [CrossRef] [PubMed]
  28. Berger, W.; Micksche, M.; Elbling, L. Effects of multidrug resistance-related ATP-binding-cassette transporter proteins on the cytoskeletal activity of cytochalasins. Exp. Cell Res. 1997, 237, 307–317. [Google Scholar] [CrossRef] [PubMed]
  29. He, S.M.; Li, C.G.; Liu, J.P.; Chan, E.; Duan, W.; Zhou, S.F. Disposition pathways and pharmacokinetics of herbal medicines in humans. Curr. Med. Chem. 2010, 17, 4072–4113. [Google Scholar] [CrossRef] [PubMed]
  30. De Leeuw, A.M.; Brouwer, A.; Knook, D.L. Sinusoidal endothelial cells of the liver: Fine structure and function in relation to age. J. Electron Microsc. Tech. 1990, 14, 218–236. [Google Scholar] [CrossRef] [PubMed]
  31. Burckhardt, G. Drug transport by organic anion transporters (OATs). Pharmacol. Ther. 2012, 136, 106–130. [Google Scholar] [CrossRef] [PubMed]
  32. Wlcek, K.; Stieger, B. ATP-binding cassette transporters in liver. BioFactors 2014, 40, 188–198. [Google Scholar] [CrossRef] [PubMed]
  33. Zhang, L.; Zuo, Z.; Lin, G. Intestinal and hepatic glucuronidation of flavonoids. Mol. Pharmacol. 2007, 4, 833–845. [Google Scholar] [CrossRef] [PubMed]
  34. Motohashi, H.; Inui, K. Multidrug and toxin extrusion family SLC47: Physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K. Mol. Asp. Med. 2013, 34, 661–668. [Google Scholar] [CrossRef] [PubMed]
  35. Stieger, B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bilesalt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb. Exp. Pharmacol. 2011, 201, 205–259. [Google Scholar]
  36. Pauli-Magnus, C.; Meier, P.J.; Stieger, B. Genetic determinants of drug-induced cholestasis andintrahepatic cholestasis of pregnancy. Semin. Liver Dis. 2010, 30, 147–159. [Google Scholar] [CrossRef] [PubMed]
  37. Meng, Q.; Liu, K. Pharmacokinetic Interactions Between Herbal Medicines and Prescribed Drugs: Focus on Drug Metabolic Enzymes and Transporters. Curr. Drug Metab. 2014, 15, 791–807. [Google Scholar] [CrossRef] [PubMed]
  38. Liu, C.X.; Yi, X.L.; Si, D.Y.; Xiao, X.F.; He, X.; Li, Y.Z. Herb-drug Interactions Involving Drug Metabolizing Enzymes and Transporters. Curr. Drug Metab. 2011, 12, 835–849. [Google Scholar] [CrossRef] [PubMed]
  39. Tamaki, H.; Satoh, H.; Hori, S.; Ohtani, H.; Sawada, Y. Inhibitory effects of herbal extracts on breast cancer resistance protein (BCRP) and structure-inhibitory potency relationship of isoflavonoids. Drug Metab. Pharmacokinet. 2010, 25, 170–179. [Google Scholar] [CrossRef] [PubMed]
  40. Ge, S.; Yin, T.; Xu, B.; Gao, S.; Hu, M. Curcumin Affects Phase II Disposition of Resveratrol through Inhibiting Efflux Transporters MRP2 and BCRP. Pharm. Res. 2016, 23, 590–592. [Google Scholar] [CrossRef] [PubMed]
  41. Zhang, S.; Yang, X.; Morris, M.E. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol. Pharmacol. 2004, 65, 1208–1216. [Google Scholar] [CrossRef] [PubMed]
  42. Perez, M.; Otero, J.A.; Barrera, B.; Prieto, J.G.; Merino, G.; Alvarez, A.I. Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: Effect on plasma and milk levels of danofloxacin in sheep. Vet. J. 2013, 196, 203–208. [Google Scholar] [CrossRef] [PubMed]
  43. Hajda, J.; Rentsch, K.M.; Gubler, C.; Steinert, H.; Stieger, B.; Fattinger, K. Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans. Eur. J. Pharm. Sci. 2010, 41, 729–735. [Google Scholar] [CrossRef] [PubMed]
  44. Dresser, G.K.; Bailey, D.G.; Leake, B.F.; Schwarz, U.I.; Dawson, P.A.; Freeman, D.J.; Kim, R.B. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin. Pharmacol. Ther. 2002, 71, 11–20. [Google Scholar] [CrossRef] [PubMed]
  45. Durr, D.; Stieger, B.; Kullak-Ublick, G.A.; Rentsch, K.M.; Steinert, H.C.; Meier, P.J.; Fattinger, K. St John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin. Pharmacol. Ther. 2000, 68, 598–604. [Google Scholar] [CrossRef] [PubMed]
  46. Cermanova, J.; Kadova, Z.; Zagorova, M.; Hroch, M.; Tomsik, P.; Nachtigal, P.; Kudlackova, Z.; Pavek, P.; Dubecka, M.; Ceckova, M.; et al. Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms. Toxicol. Appl. Pharmacol. 2015, 285, 12–22. [Google Scholar] [CrossRef] [PubMed]
  47. Qiang, F.; Kang, K.W.; Han, H.K. Repeated dosing of piperine induced gene expression of P-glycoprotein via stimulated pregnane-X-receptor activity and altered pharmacokinetics of diltiazem in rats. Biopharm. Drug Dispos. 2012, 33, 446–454. [Google Scholar] [CrossRef] [PubMed]
  48. Rigalli, J.P.; Ciriaci, N.; Arias, A.; Ceballos, M.P.; Villanueva, S.S.; Luquita, M.G.; Mottino, A.D.; Ghanem, C.I.; Catania, V.A.; Ruiz, M.L. Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: Impact on sorafenib cytotoxicity. PLoS ONE 2015, 10, e0119502. [Google Scholar] [CrossRef] [PubMed]
  49. Foster, B.C.; Foster, M.S.; Vandenhoek, S.; Krantis, A.; Budzinski, J.W.; Arnason, J.T.; Gallicano, K.D.; Choudri, S. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J. Pharm. Pharm. Sci. 2001, 4, 176–184. [Google Scholar] [PubMed]
  50. Berginc, K.; Milisav, I.; Kristl, A. Garlic flavonoids and organosulfur compounds: Impact on the hepatic pharmacokinetics of saquinavir and darunavir. Drug Metab. Pharmacokinet. 2010, 25, 521–530. [Google Scholar] [CrossRef] [PubMed]
  51. Berginc, K.; Zakelj, S.; Ursic, D.; Kristl, A. Aged garlic extract stimulates p-glycoprotein and multidrug resistance associated protein 2 mediated effluxes. Biol. Pharm. Bull. 2009, 32, 694–699. [Google Scholar] [CrossRef] [PubMed]
  52. Patel, J.; Buddha, B.; Dey, S.; Pal, D.; Mitra, A.K. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: Changes in P-gp and CYP3A4 activity. Am. J. Ther. 2004, 11, 262–277. [Google Scholar] [CrossRef] [PubMed]
  53. Kitagawa, S.; Nabekura, T.; Kamiyama, S. Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. J. Pharm. Pharmacol. 2004, 56, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
  54. Anuchapreeda, S.; Leechanachai, P.; Smith, M.M.; Ambudkar, S.V.; Limtrakul, P.N. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem. Pharmacol. 2002, 64, 573–582. [Google Scholar] [CrossRef]
  55. Romiti, N.; Pellati, F.; Nieri, P.; Benvenuti, S.; Adinolfi, B.; Chieli, E. P-Glycoprotein inhibitory activity of lipophilic constituents of Echinacea pallida roots in a human proximal tubular cell line. Planta Med. 2008, 74, 264–266. [Google Scholar] [CrossRef] [PubMed]
  56. Nabekura, T.; Yamaki, T.; Ueno, K.; Kitagawa, S. Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals. Cancer Chemother. Pharmacol. 2008, 62, 867–873. [Google Scholar] [CrossRef] [PubMed]
  57. Hellum, B.H.; Nilsen, O.G. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin. Pharmacol. Toxicol. 2008, 102, 466–475. [Google Scholar] [CrossRef] [PubMed]
  58. Perloff, M.D.; von Moltke, L.L.; Stormer, E.; Shader, R.I.; Greenblatt, D.J. Saint John’s wort: An in vitro analysis of P-glycoprotein induction due to extended exposure. Br. J. Pharmacol. 2001, 134, 1601–1608. [Google Scholar] [CrossRef] [PubMed]
  59. Etheridge, A.S.; Black, S.R.; Patel, P.R.; So, J.; Mathews, J.M. An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. Planta Med. 2007, 73, 731–741. [Google Scholar] [CrossRef] [PubMed]
  60. Demeule, M.; Brossard, M.; Turcotte, S.; Regina, A.; Jodoin, J.; Beliveau, R. Diallyl disulfide, a chemopreventive agent in garlic, induces multidrug resistance-associated protein 2 expression. Biochem. Biophys. Res. Commun. 2004, 324, 937–945. [Google Scholar] [CrossRef] [PubMed]
  61. Wlcek, K.; Koller, F.; Ferenci, P.; Stieger, B. Hepatocellular organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are inhibited by silibinin. Drug Metab. Dispos. 2013, 41, 1522–1528. [Google Scholar] [CrossRef] [PubMed]
  62. Roth, M.; Timmermann, B.N.; Hagenbuch, B. Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab. Dispos. 2011, 39, 920–926. [Google Scholar] [CrossRef] [PubMed]
  63. Wang, X.; Wolkoff, A.W.; Morris, M.E. Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab. Dispos. 2005, 33, 1666–1672. [Google Scholar] [CrossRef] [PubMed]
  64. Imanaga, J.; Kotegawa, T.; Imai, H.; Tsutsumi, K.; Yoshizato, T.; Ohyama, T.; Shirasaka, Y.; Tamai, I.; Tateishi, T.; Ohashi, K. The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharmacogenet. Genom. 2011, 21, 84–93. [Google Scholar] [CrossRef]
  65. Shirasaka, Y.; Shichiri, M.; Mori, T.; Nakanishi, T.; Tamai, I. Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions. J. Pharm. Sci. 2013, 102, 280–288. [Google Scholar] [CrossRef] [PubMed]
  66. Fuchikami, H.; Satoh, H.; Tsujimoto, M.; Ohdo, S.; Ohtani, H.; Sawada, Y. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab. Dispos. 2006, 34, 577–582. [Google Scholar] [CrossRef] [PubMed]
  67. Rebello, S.; Zhao, S.; Hariry, S.; Dahlke, M.; Alexander, N.; Vapurcuyan, A.; Hanna, I.; Jarugula, V. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur. J. Clin. Pharmacol. 2012, 68, 697–708. [Google Scholar] [CrossRef] [PubMed]
  68. Reddy, P.; Ellington, D.; Zhu, Y.; Zdrojewski, I.; Parent, S.J.; Harmatz, J.S.; Derendorf, H.; Greenblatt, D.J.; Browne, K., Jr. Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily. Br. J. Clin. Pharmacol. 2011, 72, 434–441. [Google Scholar] [CrossRef] [PubMed]
  69. Lilja, J.J.; Backman, J.T.; Laitila, J.; Luurila, H.; Neuvonen, P.J. Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin. Pharmacol. Ther. 2003, 73, 192–198. [Google Scholar] [CrossRef] [PubMed]
  70. Edwards, D.J.; Fitzsimmons, M.E.; Schuetz, E.G.; Yasuda, K.; Ducharme, M.P.; Warbasse, L.H.; Woster, P.M.; Schuetz, J.D.; Watkins, P. 6′,7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin. Pharmacol. Ther. 1999, 65, 237–244. [Google Scholar] [CrossRef]
  71. Lown, K.S.; Bailey, D.G.; Fontana, R.J.; Janardan, S.K.; Adair, C.H.; Fortlage, L.A.; Brown, M.B.; Guo, W.; Watkins, P.B. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J. Clin. Investig. 1997, 99, 2545–2553. [Google Scholar] [CrossRef] [PubMed]
  72. Bailey, D.G.; Spence, J.D.; Munoz, C.; Arnold, J.M. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991, 337, 268–269. [Google Scholar] [CrossRef]
  73. Kupferschmidt, H.H.; Fattinger, K.E.; Ha, H.R.; Follath, F.; Krahenbuhl, S. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br. J. Clin. Pharmacol. 1998, 45, 355–359. [Google Scholar] [CrossRef] [PubMed]
  74. Lilja, J.J.; Neuvonen, M.; Neuvonen, P.J. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br. J. Clin. Pharmacol. 2004, 58, 56–60. [Google Scholar] [CrossRef] [PubMed]
  75. Tapaninen, T.; Neuvonen, P.J.; Niemi, M. Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br. J. Clin. Pharmacol. 2011, 71, 718–726. [Google Scholar] [CrossRef] [PubMed]
  76. Lilja, J.J.; Juntti-Patinen, L.; Neuvonen, P.J. Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol. Clin. Pharmacol. Ther. 2004, 75, 184–190. [Google Scholar] [CrossRef] [PubMed]
  77. Jeon, H.; Jang, I.J.; Lee, S.; Ohashi, K.; Kotegawa, T.; Ieiri, I.; Cho, J.-Y.; Yoon, S.H.; Shin, S.-G.; Yu, K.-S.; et al. Apple juice greatly reduces systemic exposure to atenolol. Br. J. Clin. Pharmacol. 2013, 75, 172–179. [Google Scholar] [CrossRef] [PubMed]
  78. Yamsani, S.K.; Yamsani, M.R. Effect of silymarin pretreatment on the bioavailability of domperidone in healthy human volunteers. Drug Metabol. Drug Interact. 2014, 29, 261–267. [Google Scholar] [CrossRef] [PubMed]
  79. Han, Y.; Guo, D.; Chen, Y.; Chen, Y.; Tan, Z.R.; Zhou, H.H. Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers. Eur. J. Clin. Pharmacol. 2009, 65, 585–591. [Google Scholar] [CrossRef] [PubMed]
  80. Rajnarayana, K.; Reddy, M.S.; Vidyasagar, J.; Krishna, D.R. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004, 54, 109–113. [Google Scholar] [CrossRef] [PubMed]
  81. Han, Y.; Guo, D.; Chen, Y.; Tan, Z.R.; Zhou, H.H. Effect of continuous silymarin administration on oral talinolol pharmacokinetics in healthy volunteers. Xenobiotica 2009, 39, 694–699. [Google Scholar] [CrossRef] [PubMed]
  82. Chow, H.H.; Hakim, I.A.; Vining, D.R.; Crowell, J.A.; Cordova, C.A.; Chew, W.M.; Xu, M.J.; Hsu, C.H.; Ranger-Moore, J.; Alberts, D.S. Effects of repeated green tea catechin administration on human cytochrome P450 activity. Cancer Epidemiol. Biomark. Prev. 2006, 15, 2473–2476. [Google Scholar] [CrossRef] [PubMed]
  83. Misaka, S.; Yatabe, J.; Muller, F.; Takano, K.; Kawabe, K.; Glaeser, H.; Yatabe, M.S.; Onoue, S.; Werba, J.P.; Watanabe, H.; et al. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin. Pharmacol. Ther. 2014, 95, 432–438. [Google Scholar] [CrossRef] [PubMed]
  84. Cambria-Kiely, J.A. Effect of soy milk on warfarin efficacy. Ann. Pharmacother. 2002, 36, 1893–1896. [Google Scholar] [CrossRef] [PubMed]
  85. Johne, A.; Schmider, J.; Brockmoller, J.; Stadelmann, A.M.; Stormer, E.; Bauer, S.; Scholler, G.; Langheinrich, M.; Roots, I. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J. Clin. Psychopharmacol. 2002, 22, 46–54. [Google Scholar] [CrossRef] [PubMed]
  86. Van Strater, A.C.; Bogers, J.P. Interaction of St John’s wort (Hypericum perforatum) with clozapine. Int. Clin. Psychopharmacol. 2012, 27, 121–124. [Google Scholar] [CrossRef] [PubMed]
  87. Barone, G.W.; Gurley, B.J.; Ketel, B.L.; Lightfoot, M.L.; Abul-Ezz, S.R. Drug interaction between St. John’s wort and cyclosporine. Ann. Pharmacother. 2000, 34, 1013–1016. [Google Scholar] [CrossRef] [PubMed]
  88. Wang, Z.; Hamman, M.A.; Huang, S.M.; Lesko, L.J.; Hall, S.D. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin. Pharmacol. Ther. 2002, 71, 414–420. [Google Scholar] [CrossRef] [PubMed]
  89. Piscitelli, S.C.; Burstein, A.H.; Chaitt, D.; Alfaro, R.M.; Falloon, J. Indinavir concentrations and St John’s wort. Lancet 2000, 355, 547–548. [Google Scholar] [CrossRef]
  90. Pathak, A.; Leger, P.; Bagheri, H.; Senard, J.M.; Boccalon, H.; Montastruc, J.L. Garlic interaction with fluindione: A case report. Therapie 2003, 58, 380–381. [Google Scholar] [CrossRef] [PubMed]
  91. Gorski, J.C.; Huang, S.M.; Pinto, A.; Hamman, M.A.; Hilligoss, J.K.; Zaheer, N.A.; Desai, M.; Miller, M.; Hall, S.D. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin. Pharmacol. Ther. 2004, 75, 89–100. [Google Scholar] [CrossRef] [PubMed]
  92. Markowitz, J.S.; Donovan, J.L.; Lindsay DeVane, C.; Sipkes, L.; Chavin, K.D. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J. Clin. Psychopharmacol. 2003, 23, 576–581. [Google Scholar] [CrossRef] [PubMed]
  93. Kim, K.A.; Park, P.W.; Park, J.Y. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur. J. Clin. Pharmacol. 2009, 65, 609–614. [Google Scholar] [CrossRef] [PubMed]
  94. Uchida, S.; Yamada, H.; Li, X.D.; Maruyama, S.; Ohmori, Y.; Oki, T.; Watanabe, H.; Umegaki, K.; Ohashi, K.; Yamada, S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J. Clin. Pharmacol. 2006, 46, 1290–1298. [Google Scholar] [CrossRef] [PubMed]
  95. Fan, L.; Mao, X.Q.; Tao, G.Y.; Wang, G.; Jiang, F.; Chen, Y.; Li, Q.; Zhang, W.; Lei, H.P.; Hu, D.L.; et al. Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica 2009, 39, 249–254. [Google Scholar] [CrossRef] [PubMed]
  96. Yin, O.Q.; Tomlinson, B.; Waye, M.M.; Chow, A.H.; Chow, M.S. Pharmacogenetics and herb-drug interactions: Experience with Ginkgo biloba and omeprazole. Pharmacogenetics 2004, 14, 841–850. [Google Scholar] [CrossRef] [PubMed]
  97. Malati, C.Y.; Robertson, S.M.; Hunt, J.D.; Chairez, C.; Alfaro, R.M.; Kovacs, J.A.; Penzak, S.R. Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants. J. Clin. Pharmacol. 2012, 52, 932–979. [Google Scholar] [CrossRef] [PubMed]
  98. Hanley, M.J.; Cancalon, P.; Widmer, W.W.; Greenblatt, D.J. The effect of grapefruit juice on drug disposition. Exp. Opin. Drug Metab. Toxicol. 2011, 7, 267–286. [Google Scholar] [CrossRef] [PubMed]
  99. Seden, K.; Dickinson, L.; Khoo, S.; Back, D. Grapefruit-drug interactions. Drugs 2010, 70, 2373–2407. [Google Scholar] [CrossRef] [PubMed]
  100. Takanaga, H.; Ohnishi, A.; Matsuo, H.; Sawada, Y. Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells. Biol. Pharm. Bull. 1998, 21, 1062–1066. [Google Scholar] [CrossRef] [PubMed]
  101. De Castro, W.V.; Mertens-Talcott, S.; Derendorf, H.; Butterweck, V. Grapefruit juice–drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J. Pharm. Sci. 2007, 96, 2808–2817. [Google Scholar] [CrossRef] [PubMed]
  102. Soldner, A.; Christians, U.; Susanto, M.; Wacher, V.J.; Silverman, J.A.; Benet, L.Z. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm. Res. 1999, 16, 478–485. [Google Scholar] [CrossRef] [PubMed]
  103. Panchagnula, R.; Bansal, T.; Varma, M.V.; Kaul, C.L. Co-treatment with grapefruit juice inhibits while chronic administration activates intestinal P-glycoprotein-mediated drug efflux. Pharmazie 2005, 60, 922–927. [Google Scholar] [PubMed]
  104. Parker, R.B.; Yates, C.R.; Soberman, J.E.; Laizure, S.C. Effects of grapefruit juice on intestinal P-glycoprotein: Evaluation using digoxin in humans. Pharmacotherapy 2003, 23, 979–987. [Google Scholar] [CrossRef] [PubMed]
  105. An, G.; Mukker, J.K.; Derendorf, H.; Frye, R.F. Enzyme- and transporter-mediated beverage-drug interactions: An update on fruit juices and green tea. J. Clin. Pharmacol. 2015, 55, 1313–1331. [Google Scholar] [CrossRef] [PubMed]
  106. Shirasaka, Y.; Suzuki, K.; Nakanishi, T.; Tamai, I. Differential effect of grapefruit juice on intestinal absorption of statins due to inhibition of organic anion transporting polypeptide and/or P-glycoprotein. J. Pharm. Sci. 2011, 100, 3843–3853. [Google Scholar] [CrossRef] [PubMed]
  107. Mitsunaga, Y.; Takanaga, H.; Matsuo, H.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur. J. Pharmacol. 2000, 395, 193–201. [Google Scholar] [CrossRef]
  108. Honda, Y.; Ushigome, F.; Koyabu, N.; Morimoto, S.; Shoyama, Y.; Uchiumi, T.; Kuwano, M.; Ohtani, H.; Sawada, Y. Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux. Br. J. Pharmacol. 2004, 143, 856–864. [Google Scholar] [CrossRef] [PubMed]
  109. Malhotra, S.; Bailey, D.G.; Paine, M.F.; Watkins, P.B. Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins. Clin. Pharmacol. Ther. 2001, 69, 14–23. [Google Scholar] [CrossRef] [PubMed]
  110. Shirasaka, Y.; Shichiri, M.; Murata, Y.; Mori, T.; Nakanishi, T.; Tamai, I. Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption. Drug Metab. Dispos. 2013, 41, 615–621. [Google Scholar] [CrossRef] [PubMed]
  111. Dolton, M.J.; Roufogalis, B.D.; McLachlan, A.J. Fruit juices as perpetrators of drug interactions: The role of organic anion-transporting polypeptides. Clin. Pharmacol. Ther. 2012, 92, 622–630. [Google Scholar] [CrossRef] [PubMed]
  112. Saller, R.; Melzer, J.; Reichling, J.; Brignoli, R.; Meier, R. An updated systematic review of the pharmacology of silymarin. Forsch. Komplement. 2007, 14, 70–80. [Google Scholar] [CrossRef]
  113. Simanek, V.; Kren, V.; Ulrichova, J.; Vicar, J.; Cvak, L. Silymarin: What is in the name...? An appeal for a change of editorial policy. Hepatology 2000, 32, 442–444. [Google Scholar] [CrossRef] [PubMed]
  114. Saller, R.; Brignoli, R.; Melzer, J.; Meier, R. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch. Komplement. 2008, 15, 9–20. [Google Scholar] [CrossRef] [PubMed]
  115. Loguercio, C.; Festi, D. Silybin and the liver: From basic research to clinical practice. World J. Gastroenterol. 2011, 17, 2288–2301. [Google Scholar] [CrossRef] [PubMed]
  116. Ganzert, M.; Felgenhauer, N.; Schuster, T.; Eyer, F.; Gourdin, C.; Zilker, T. Silibinin und Kombination von Silibinin und Penicillin im Vergleich [Amatoxin poisoning—comparison of silibinin with a combination of silibinin and penicillin]. Dtsch. Med. Wochenschr. 2008, 133, 2261–2267. [Google Scholar] [CrossRef] [PubMed]
  117. Garcia, J.; Costa, V.M.; Carvalho, A.; Baptista, P.; de Pinho, P.G.; de Lourdes Bastos, M.; Carvalho, F. Amanita phalloides poisoning: Mechanisms of toxicity and treatment. Food Chem. Toxicol. 2015, 86, 41–55. [Google Scholar] [CrossRef] [PubMed]
  118. Murtaza, G.; Latif, U.; Najam-Ul-Haq, M.; Sajjad, A.; Karim, S.; Akhtar, M.; Hussain, I. Resveratrol: An active natural compound in red wines for health. J. Food Drug Anal. 2013, 21, 1–12. [Google Scholar]
  119. Letschert, K.; Faulstich, H.; Keller, D.; Keppler, D. Molecular characterization and inhibition ofamanitin uptake into human hepatocytes. Toxicol. Sci. 2006, 91, 140–149. [Google Scholar] [CrossRef] [PubMed]
  120. Fehrenbach, T.; Cui, Y.; Faulstich, H.; Keppler, D. Characterization of the transport of the bicyclic peptide phalloidin by human hepatic transport proteins. Naunyn Schmiedeberg’s Arch. Pharmacol. 2013, 368, 415–420. [Google Scholar] [CrossRef] [PubMed]
  121. Meier-Abt, F.; Faulstich, H.; Hagenbuch, B. Identification of phalloidin uptake systems of rat and human liver. Biochim. Biophys. Acta 2004, 1664, 64–69. [Google Scholar] [CrossRef] [PubMed]
  122. Gundala, S.; Wells, L.D.; Milliano, M.T.; Talkad, V.; Luxon, B.A.; Neuschwander-Tetri, B.A. The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin. Arch. Toxicol. 2004, 78, 68–73. [Google Scholar] [CrossRef] [PubMed]
  123. Ferenci, P.; Scherzer, T.M.; Kerschner, H.; Rutter, K.; Beinhardt, S.; Hofer, H.; Schöniger-Hekele, M.; Holzmann, H.; Steindl-Munda, P. Silibinin is a potent antiviralagent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008, 135, 1561–1567. [Google Scholar] [CrossRef] [PubMed]
  124. Biermer, M.; Berg, T. Rapid suppression of hepatitis C viremia induced by intravenous silibinin plus ribavirin. Gastroenterology 2009, 137, 390–391. [Google Scholar] [CrossRef] [PubMed]
  125. Rutter, K.; Scherzer, T.M.; Beinhardt, S.; Kerschner, H.; Stattermayer, A.F.; Hofer, H.; Popow-Kraupp, T.; Steindl-Munda, P.; Ferenci, P. Intravenous silibinin as ‘rescue treatment’ for on-treatment non-responders to pegylated interferon/ribavirin combination therapy. Antivir. Ther. 2011, 16, 1327–1333. [Google Scholar] [CrossRef] [PubMed]
  126. Braun, D.L.; Rauch, A.; Aouri, M.; Durisch, N.; Eberhard, N.; Anagnostopoulos, A.; Ledergerber, B.; Müllhaupt, B.; Metzner, K.J.; Decosterd, L.; et al. A lead-in with silibinin prior to triple therapy translates into favorable treatment outcomes in difficult-to-treat HIV/hepatitis C coinfected patients. PLoS ONE 2015, 10, e0133028. [Google Scholar] [CrossRef] [PubMed]
  127. Stieger, B.; Heger, M.; de Graaf, W.; Paumgartner, G.; van Gulik, T. The emerging role of transport systems in liver function tests. Eur. J. Pharmacol. 2012, 675, 1–5. [Google Scholar] [CrossRef] [PubMed]
  128. Misaka, S.; Kawabe, K.; Onoue, S.; Werba, J.P.; Giroli, M.; Watanabe, H.; Yamada, S. Green tea extract affects the cytochromeP450 3A activity and pharmacokinetics of simvastatin in rats. Drug Metab. Pharmacokinet. 2013, 28, 514–518. [Google Scholar] [CrossRef] [PubMed]
  129. Jager, W.; Winter, O.; Halper, B.; Salamon, A.; Sartori, M.; Gajdzik, L.; Hamilton, G.; Theyer, G.; Graf, J.; Thalhammer, T. Modulation of liver canalicular¨ transport processes by the tyrosine-kinase inhibitor genistein: Implications of genistein metabolism in the rat. Hepatology 1997, 26, 1467–1476. [Google Scholar] [CrossRef] [PubMed]
  130. Cheng, T.O. Potential interaction between soy milk and warfarin. Am. Fam. Physician 2004, 70, 1231. [Google Scholar] [PubMed]
  131. Kasper, S.; Caraci, F.; Forti, B.; Drago, F.; Aguglia, E. Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression. Eur. Neuropsychopharmacol. 2010, 20, 747–765. [Google Scholar] [CrossRef] [PubMed]
  132. Nahrstedt, A.; Butterweck, V. Lessons learned from herbal medicinal products: The example of St. John’s wort. J. Nat. Prod. 2010, 73, 1015–1021. [Google Scholar] [CrossRef] [PubMed]
  133. Butterweck, V.; Schmidt, M. St. John’s wort: Role of active compounds for its mechanism of action and efficacy. Wien. Med. Wochenschr. 2007, 157, 356–361. [Google Scholar] [CrossRef] [PubMed]
  134. Schmidt, M.; Butterweck, V. The mechanisms of action of St. John’s wort: An update. Wien. Med. Wochenschr. 2015, 165, 229–235. [Google Scholar] [CrossRef] [PubMed]
  135. Zhou, S.; Chan, E.; Pan, S.Q.; Huang, M.; Lee, E.J. Pharmacokinetic interactions of drugs with St. John’s wort. J. Psychopharmacol. 2004, 18, 262–276. [Google Scholar] [CrossRef] [PubMed]
  136. Russo, E.; Scicchitano, F.; Whalley, B.J.; Mazzitello, C.; Ciriaco, M.; Esposito, S.; Patanè, M.; Upton, R.; Pugliese, M.; Chimirri, S.; et al. Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug–drug interactions. Phytother. Res. 2014, 28, 643–655. [Google Scholar] [CrossRef] [PubMed]
  137. Moore, L.B.; Goodwin, B.; Jones, S.A.; Wisely, G.B.; Serabjit-Singh, C.J.; Willson, T.M.; Collins, J.L.; Kliewer, S.K. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad. Sci. USA 2000, 97, 7500–7502. [Google Scholar] [CrossRef] [PubMed]
  138. Obach, R.S. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression. J. Pharmacol. Exp. Ther. 2000, 294, 88–95. [Google Scholar] [PubMed]
  139. Ruschitzka, F.; Meier, P.J.; Turina, M.; Luscher, T.F.; Noll, G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000, 355, 548–549. [Google Scholar] [CrossRef]
  140. Breidenbach, T.; Kliem, V.; Burg, M.; Radermacher, J.; Hoffmann, M.W.; Klempnauer, J. Profound drop of cyclosporin A whole blood trough levels caused by St. John’s wort (Hypericum perforatum). Transplantation 2000, 69, 2229–2230. [Google Scholar] [CrossRef] [PubMed]
  141. Ernst, E. St. John’s wort supplements endanger the success of organ transplantation. Arch. Surg. 2002, 137, 316–319. [Google Scholar] [CrossRef] [PubMed]
  142. Borrelli, F.; Izzo, A.A. Herb–drug interactions with St. John’s wort (Hypericum perforatum): An update on clinical observations. AAPS J. 2009, 11, 710–727. [Google Scholar] [CrossRef] [PubMed]
  143. Rahimi, R.; Abdollahi, M. An update on the ability of St. John’s wort to affect the metabolism ofother drugs. Exp. Opin. Drug Metab. Toxicol. 2012, 8, 691–708. [Google Scholar] [CrossRef] [PubMed]
  144. Mannel, M. Drug interactions with St. John’s wort: Mechanisms and clinical implications. Drug Saf. 2004, 27, 773–797. [Google Scholar] [CrossRef] [PubMed]
  145. Posadzki, P.; Watson, L.; Ernst, E. Herb–drug interactions: An overview of systematic reviews. Br. J. Clin. Pharmacol. 2013, 75, 603–618. [Google Scholar] [CrossRef] [PubMed]
  146. Pan, S.Y.; Litscher, G.; Gao, S.H.; Zhou, S.F.; Yu, Z.L.; Chen, H.Q.; Zhang, S.F.; Tang, M.K.; Sun, J.N.; Ko, K.M. Historical perspective of traditional indigenous medical practices: The current renaissance and conservation of herbal resources. Evid.-Based Complement. Altern. Med. 2014, 2014, 525340. [Google Scholar] [CrossRef] [PubMed]
  147. Pan, S.Y.; Litscher, G.; Chan, K.; Yu, Z.L.; Chen, H.Q.; Ko, K.M. Traditional medicines in the world: Where to go next? Evid. Based Complement. Alternat. Med. 2014, 2014, 739895. [Google Scholar] [CrossRef] [PubMed]
  148. Hong, M.; Li, S.; Tan, H.Y.; Wang, N.; Tsao, S.W.; Feng, Y. Current status of herbal medicines inchronic liver disease therapy: The biological effects, molecular targets and future prospects. Int. J. Mol. Sci. 2015, 16, 28705–28745. [Google Scholar] [CrossRef] [PubMed]
  149. Seeff, L.B.; Curto, T.M.; Szabo, G.; Everson, G.T.; Bonkovsky, H.L.; Dienstag, J.L.; Shiffman, M.L.; Lindsay, K.L.; Lok, A.S.; Di Bisceglie, A.M.; et al. Herbal product use bypersons enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology 2008, 47, 605–612. [Google Scholar] [CrossRef] [PubMed]
  150. Struppler, A.; Rossler, H. Choleretic effect of artichoke extract. Med. Monatsschrift 1957, 11, 221–223. (In German) [Google Scholar]
  151. Kraft, K. Artichoke leaf extract—Recent findings reflecting effects on lipid metabolism, liver and gastrointestinal tracts. Phytomedicine 1997, 4, 369–378. [Google Scholar] [CrossRef]
  152. Preziosi, P.; Loscalzo, B. Pharmacological properties of 1, 4 dicaffeylquinic acid, the active principle of Cynara scolimus. Arch. Int. Pharmacodyn. Ther. 1958, 117, 63–80. [Google Scholar] [PubMed]
  153. Kirchhoff, R.; Beckers, C.; Kirchhoff, G.M.; Trinczek-Gartner, H.; Petrowicz, O.; Reimann, H.J. Increase in choleresis by means of artichoke extract. Phytomedicine 1994, 1, 107–115. [Google Scholar] [CrossRef]
  154. Salem, M.B.; Affes, H.; Ksouda, K.; Dhouibi, R.; Sahnoun, Z.; Hammami, S.; Zeghal, K.M. Pharmacological studies of artichoke leaf extract and their health benefits. Plant Foods Hum. Nutr. 2015, 70, 441–453. [Google Scholar] [CrossRef] [PubMed]
  155. Zhang, Z.Y.; Si, D.Y.; Yi, X.L.; Liu, C.X. Inhibitory effect of medicinal plant-derived carboxylic acids on the human transporters hOAT1, hOAT3, hOATP1B1, and hOATP2B1. Chin. J. Nat. Med. 2014, 12, 131–138. [Google Scholar] [CrossRef]
  156. Tang, L.; Li, Y.; Chen, W.Y.; Zeng, S.; Dong, L.N.; Peng, X.J.; Jiang, W.; Hu, M.; Liu, Z.Q. Breast cancer resistance protein-mediated efflux of luteolin glucuronides in HeLa cells overexpressing UDP-glucuronosyltransferase 1A9. Pharm. Res. 2014, 31, 847–860. [Google Scholar] [CrossRef] [PubMed]
  157. Tome-Carneiro, J.; Larrosa, M.; Yánez-Gascõn, M.J.; Dávalos, A.; Gil-Zamorano, J.; Gonzálvez, M.; García-Almagro, F.J.; Ruiz Ros, J.A.; Tomás-Barberán, F.A.; Espín, J.C.; et al. One-year’ supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol. Res. 2013, 72, 69–82. [Google Scholar] [PubMed]
  158. Wahab, A.; Gao, K.; Jia, C.; Zhang, F.; Tian, G.; Murtaza, G.; Chen, J. Significance of resveratrol in clinical management of chronic diseases. Moleicules 2017, 22, 1329. [Google Scholar] [CrossRef] [PubMed]
  159. Urpí-Sarda, M.; Jàuregui, O.; Lamuela-Raventós, R.M.; Jaeger, W.; Miksits, M.; Covas, M.I.; Andres-Lacueva, C. Uptake of diet resveratrol into the human low-density lipoprotein. Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry. Anal. Chem. 2005, 77, 3149–3155. [Google Scholar] [CrossRef] [PubMed]
  160. Walle, T.; Hsieh, F.; DeLegge, M.H.; Oatis, J.E., Jr.; Walle, U.K. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 2004, 32, 1377–1382. [Google Scholar] [CrossRef] [PubMed]
  161. Van de Wetering, K.; Burkon, A.; Feddema, W.; Bot, A.; de Jonge, H.; Somoza, V.; Borst, P. Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol. Mol. Pharmacol. 2009, 75, 876–885. [Google Scholar] [CrossRef] [PubMed]
  162. Henry, C.; Vitrac, X.; Decendit, A.; Ennamany, R.; Krisa, S.; Merillon, J.M. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem. 2005, 53, 798–803. [Google Scholar] [CrossRef] [PubMed]
  163. Al-Abd, A.M.; Mahmoud, A.M.; El-Sherbiny, G.A.; El-Moselhy, M.A.; Nofal, S.M.; El-Latif, H.A.; El-Eraky, W.I.; El-Shemy, H.A. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro. Cell Prolif. 2011, 44, 591–601. [Google Scholar] [CrossRef] [PubMed]
  164. Jia, Y.; Liu, Z.; Huo, X.; Wang, C.; Meng, Q.; Liu, Q.; Sun, H.; Sun, P.; Yang, X.; Shu, X.; et al. Enhancement effect of resveratrol on the intestinal absorption of bestatin by regulating PEPT1, MDR1 and MRP2 in vivo and in vitro. Int. J. Pharm. 2015, 495, 588–598. [Google Scholar] [CrossRef] [PubMed]
  165. Zhu, Y.; He, W.; Gao, X.; Li, B.; Mei, C.; Xu, R.; Chen, H. Resveratrol overcomes gefitinib resistance by increasing the intracellular gefitinib concentration and triggering apoptosis, autophagy and senescence in PC9/G NSCLC cells. Sci. Rep. 2015, 5, 17730. [Google Scholar] [CrossRef] [PubMed]
  166. Patel, K.R.; Brown, V.A.; Jones, D.J.; Britton, R.G.; Hemingway, D.; Miller, A.S.; West, K.P.; Booth, T.D.; Perloff, M.; Crowell, J.A.; et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010, 70, 7392–7399. [Google Scholar] [CrossRef] [PubMed]
  167. Burkon, A.; Somoza, V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides—Two novel resveratrol metabolites in human plasma. Mol. Nutr. Food Res. 2008, 52, 549–557. [Google Scholar] [CrossRef] [PubMed]
  168. Chow, H.H.; Garland, L.L.; Hsu, C.H.; Vining, D.R.; Chew, W.M.; Miller, J.A.; Perloff, M.; Crowell, J.A.; Alberts, D.S. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev. Res. 2010, 3, 1168–1175. [Google Scholar] [CrossRef] [PubMed]
  169. Srovnalova, A.; Svecarova, M.; Zapletalova, M.K.; Anzenbacher, P.; Bachleda, P.; Anzenbacherova, E.; Dvorak, Z. Effects of anthocyanidins and anthocyanins on the expression and catalytic activities of CYP2A6, CYP2B6, CYP2C9, and CYP3A4 in primary human hepatocytes and human liver microsomes. J. Agric. Food Chem. 2014, 62, 789–797. [Google Scholar] [CrossRef] [PubMed]
  170. Szotaková, B.; Bártíkova, H.; Hlaváćcovă, J.; Bouśovă, I.; Skálová, L. Inhibitory effect of anthocyanidinś on hepatic glutathione S-transferase, UDP-glucuronosyltransferase and carbonyl reductase activities in rat and human. Xenobiotica 2013, 43, 679–685. [Google Scholar] [CrossRef] [PubMed]
  171. Dreiseitel, A.; Oosterhuis, B.; Vukman, K.V.; Schreier, P.; Oehme, A.; Locher, S.; Hajak, G.; Sand, P.G. Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1. Br. J. Pharmacol. 2009, 158, 1942–1950. [Google Scholar] [CrossRef] [PubMed]
  172. Srinivas, N.R. Cranberry juice ingestion and clinical drug-drug interaction potentials: Review of case studies and perspectives. J. Pharm. Pharm. Sci. 2013, 16, 289–303. [Google Scholar] [CrossRef] [PubMed]
  173. Hamann, G.L.; Campbell, J.D.; George, C.M. Warfarin-cranberry juice interaction. Ann. Pharmacother. 2011, 45, e17. [Google Scholar] [CrossRef] [PubMed]
  174. Riha, J.; Brenner, S.; Srovnalova, A.; Klameth, L.; Dvorak, Z.; Jäger, W.; Thalhammer, T. Effects of anthocyans on the expression of organic anion transporting polypeptides (SLCOs/OATPs) in primary human hepatocytes. Food Funct. 2015, 6, 772–779. [Google Scholar] [CrossRef] [PubMed]
  175. Hansen, T.S.; Nilsen, O.G. Echinacea purpurea and P-glycoprotein drug transport in Caco-2 cells. Phytother. Res. 2009, 23, 86–91. [Google Scholar] [CrossRef] [PubMed]
  176. Velpandian, T.; Jasuja, R.; Bhardwaj, R.K.; Jaiswal, J.; Gupta, S.K. Piperine in food: Interference in the pharmacokinetics of phenytoin. Eur. J. Drug Metab. Pharmacokinet. 2001, 26, 241–247. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: Not Available.
Figure 1. A schematic representation of transporters in human intestine and liver for movement of drugs, botanical supplements and bile salts. Note: P-gp, P-glycoprotein; OATP, organic anion transporting polypeptide; BSEP, bile salt export pump; ABC, ATP-binding cassette; ASBT, apical sodium-dependent bile acid transporter; OST, organic solute transporter; MRP, multidrug resistance-associated protein; MDR, multidrug resistance protein; NTCP, sodium taurocholate cotransporting polypeptide; MATE: multidrug and toxin extruder; OCT, organic cation transporter; OAT, organic anion transporter; MCT, monocarboxylase transporter; HPT, human intestinal peptide-associated transporter; PEPT, peptide transporter.
Figure 1. A schematic representation of transporters in human intestine and liver for movement of drugs, botanical supplements and bile salts. Note: P-gp, P-glycoprotein; OATP, organic anion transporting polypeptide; BSEP, bile salt export pump; ABC, ATP-binding cassette; ASBT, apical sodium-dependent bile acid transporter; OST, organic solute transporter; MRP, multidrug resistance-associated protein; MDR, multidrug resistance protein; NTCP, sodium taurocholate cotransporting polypeptide; MATE: multidrug and toxin extruder; OCT, organic cation transporter; OAT, organic anion transporter; MCT, monocarboxylase transporter; HPT, human intestinal peptide-associated transporter; PEPT, peptide transporter.
Molecules 22 01699 g001
Table 1. The selective in vitro studies revealing the role of various botanical supplements in the inhibition/induction of various transporters.
Table 1. The selective in vitro studies revealing the role of various botanical supplements in the inhibition/induction of various transporters.
TransporterBotanicals and Their EffectReferences
BCRPInhibitorCimicifuga racemosa extract[39]
Curcumin (Curcuma longa flavonoid)[40]
Kaempferol (Gingko biloba flavonoid)[41]
Naringenin (Grapefruit flavonoid)[41]
Genistein (Glycine max flavonoid)[42]
Silybum marianum extract[39]
MDR1InducerGarlic extract[43]
Grapefruit juice[44]
Hypericum perforatum extract[45]
Bodine (Peumus boldo flavonoid)[46]
Piperine (Piper nigrum flavonoid)[47]
Genistein (Glycine max flavonoid)[48]
InhibitorGarlic extract[49]
Tangeretin, nobiletin, rutin, allicin (Garlic flavonoid)[50,51,52]
epigallocatechin gallate, epicatechin gallate, quercetin (Camellia sinensis flavonoid)[53]
Curcumin (Curcuma longa flavonoid)[54]
Echinacea extract[55]
Glycyrrhetinic acid (Glycyrrhiza glabra flavonoid)[56]
Gingko biloba extract[57]
Hypericum perforatum extract[58]
Panax ginseng extract[59]
MRP1InhibitorGlycyrrhetinic acid (Glycyrrhiza glabra flavonoid)[56]
MRP2InducerGarlic extract[51]
Diallyl disulfide (Garlic flavonoid)[60]
Bodine (Peumus boldo flavonoid)[46]
Genistein (Glycine max flavonoid)[48]
InhibitorCurcumin (Curcuma longa flavonoid)[40]
Silybin A + silybin B (Silybum marianum flavonoids)[61]
OATP1A2InhibitorCamellia sinensis extract, epicatechin gallate, epigallocatechin gallate[62]
Grapefruit juice[44]
Orange juice[44]
OATP1B1InhibitorEpigallocatechin gallate, epicatechin gallate (Camellia sinensis flavonoid)[62]
Genistein (Glycine max flavonoid)[63]
Silybin A + silybin B (Silybum marianum flavonoids)[61]
OATP1B3InhibitorSilybin A + silybin B (Silybum marianum flavonoids)[61]
OATP2B1InhibitorApple juice[64]
Apple juice, phloridzin, phloretin[64,65]
Camellia sinensis extract, epicatechin gallate, epigallocatechin gallate[66]
Cimicifuga racemosa extract[66]
Echinacea extract[66]
Kaempferol (Gingko biloba flavonoid)[66]
Grapefruit juice[44]
Orange juice[44]
Glycine max extract[66]
Silybin A + silybin B (Silybum marianum flavonoids)[61]
NTCPInhibitorApple juice[44]
BSEPInducerBodine (Peumus boldo flavonoid)[46]
Table 2. Reported interactions between the clinically prescribed drugs and botanical supplements.
Table 2. Reported interactions between the clinically prescribed drugs and botanical supplements.
DrugsBotanical SupplementsEffect on Transporters/EnzymesPharmacokinetic ChangeRefs.
AUCCmaxPR
AliskirenGrapefruit juice↓ intestinal OATP1A2-[67]
Atorvastatin↓ CYP3A4--[68]
Celiprolol↓ OATPs-[69]
Cyclosporine↓ CYP3A4-[70]
Felodipine↓ CYP3A4[71]
Fexofenadine↓ intestinal OATP1A2-[44]
Nifedipine↓ CYPs-[72]
Saquinavir↓ CYP3A4-[73]
Simvastatin↓ CYP3A4-[74]
AliskirenOrange juice↓ OATP2B1[75]
Celiprolol↓ OATPs-[76]
Fexofenadine↓ OATP1A2-[44]
AliskirenApple juice↓ OATP2B1[75]
Atenolol↓ OATP2B1-[77]
Fexofenadine↓ OATP1A2-[44]
Fexofenadine↓ OATP2B1-[67]
DomperidoneSilybum marianum↓ CYP3A4, ↓ MDR1-[78]
Losartan↓ CYP3A4-[79]
Metronidazole↑ MDR1, ↑ CYP3A4-[80]
Talinol↓ MDR1-[81]
BuspironeCamelia sinensis↓ CYP3A4--[82]
Nadolol↓ OATP1A2[83]
WarfarinSoybean↓ OATPs--[84]
AmitriptylineHypericum perforatum↑ MDR1, ↑ CYP3A4-[85]
Clozapine↑ MDR1, ↑ CYPs--[86]
Cyclosporine↑ MDR1, ↑ CYP3A4--[87]
Digoxin↑ MDR1, ↑ CYP3A4-[45]
Fexofenadine (single dose)↓ MDR1-[88]
Fexofenadine (multiple dosing)↓ MDR1-[88]
Indinavir↑ MDR1, ↑ CYP3A4--[89]
FluindioneAllium sativum↑ CYPs--[90]
Saquinavir↑ intestinal MDR1 [43]
MidazolamEchinacea pupurea↑ hepatic CYP3A--[91]
AlprazolamGingko biloba↓ CYP3A4--[92]
Midazolam↑ CYP3A-[93]
Midazolam↓ CYP3A4--[94]
Talinol↓MDR1-[95]
Omeprazole↑ CYP2C19--[96]
MidazolamPanax ginseng↑ CYP3A-[97]
AUC: Area under curve, Cmax: maximum plasma drug concentration, PR: pharmacodynamic response, ↓: inhibition/decrease, ↑: induction/increase, -: not reported.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top