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Quercetin (QUE) is a primary polyphenol in the flavonoid family. It is categorized as one of the six subclasses of flavonoid compounds. As an abundant form of flavonoid molecules, quercetins are ubiquitously distributed in various dietary plants, including apples, berries, onions, bananas, tomatoes, and grapes. Furthermore, it is affordably marketed in the form of dietary supplement tablets. QUE is relatively lipophilic with low solubility in the water. Withal, QUE glucoside is more water soluble than the aglycone, and its absorption is limited to sodium-dependent glucose transporter-1 (SGLT-1); however, glucose transporter-2 (GLUT-2)-dependent absorption is also a significant contributor. Following absorption, QUE undergoes extensive metabolism in the liver, generating numerous metabolites. Data on the bioavailability of QUE differ substantially depending on the methods used for measuring QUE level. Pharmacokinetic interactions of QUE and its metabolites on cytochrome P450 enzymes have been studied extensively, but the results among the studies were inconsistent, such as weak inhibition toward CYP3A4 and no inhibition of CYP2D6 activity. Additionally, inhibition affects ATP- (adenosine triphosphate) binding cassette (ABC). Based on the pharmacokinetics profile, QUE has variable bioavailability based on the polymorphism of intestinal enzymes and transporters.
College of Medicine, Sulaiman Al Rajhi University, Al-Qassim, Kingdom of Saudi Arabia
Wahyu Choirur Rizky
College of Medicine, Sulaiman Al Rajhi University, Al-Qassim, Kingdom of Saudi Arabia
Mazhar Mushtaq*
Department of Basic Medical Sciences, Sulaiman Al Rajhi University, Al-Qassim, Kingdom of Saudi Arabia
*Address all correspondence to: dr_hcg@yahoo.com
1. Introduction
Quercetin (QUE) (3,3′,4′,5,7-pentahydroxyflavone) is a naturally occurring plant-based polyphenolic compound that belongs to the flavonols subclass of flavonoids. Within the flavonols subclass, other main compounds include isorhamnetin, myricetin, and kaempferol. Flavonoids, the primary secondary metabolites synthesized by various plants, play essential roles in plant defense and signaling in response to biological and environmental stressors [1]. Within plant cells, QUE and other flavonoids typically accumulate in the form of glycosides, the most common forms of which are QUE-3-glucoside and rutin [2]. Despite its abundance in various fruits and vegetables, its richest sources are onions, apples, grapes, berries, and tea [2, 3].
In recent years, there has been an increase in research interest in quercetin. QUE is the most studied phytochemical and an important flavonoid for research [4]. Specifically, a growing body of well-documented evidence suggests numerous therapeutic and prophylactic roles of QUE in various diseases (e.g., neurodegenerative, infectious, and cardiovascular) and other bioactive processes (e.g., antimicrobial, antiviral, antioxidants, and antiaging) [5, 6]. Most recently, numerous clinical trials have been conducted to examine the roles of QUE as an adjunct therapy for the coronavirus disease 2019 (COVID-19) [7].
Nowadays, QUE is also widely marketed in various pharmaceutical and dietary supplemental products in the form of capsules, tablets, and liquid drops. Some studies have examined the effect of incorporating QUE in different food products, for example, snack bars and chewing gums. More recently, QUE has been extensively studied for topical formulation, particularly in the nanocrystalline form, to enhance its dermal bioavailability [8, 9]. In line with this, it is essential to understand the pharmacokinetic properties of QUE in various formulations to determine the optimal dosage and carrier system that maximizes QUE uptake and its bioavailability [3, 10]. For instance, chewing bars, lozenges, and gums have certain advantages over traditional capsule formulations regarding rapid and efficient uptake in the bloodstream due to buccal absorption, thereby avoiding first-pass metabolism by the liver and intestinal cells. In this chapter, we will elaborate deeply on the pharmacokinetics properties of quercetin.
QUE is a plant pigment classified as a flavonoid compound with a polyphenol or pentahydroxyflavone structure (C15H10O7) [11]. Flavonoids are classified into six classes in relation to their chemical structure, including flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanidin [12]. It belongs to the class of flavonols that cannot be synthesized in the human body. Naturally, it is ubiquitous in plant food sources (primarily as glycosides) such as onions, apples, citrus fruits, green leafy vegetables, kale, broccoli grapes, cherries, berries, buckwheat, and green tea. Among them, onions and apples are the most essential sources of QUE in the human diet. Likewise, it has been considered a significant bioflavonoid compound in the human diet and has several benefits for human health [13]. Onions primarily contain QUE-4-glucoside and QUE-3,4′-diglucoside. On the other hand, apples contain QUE-3-O-glucoside, QUE-3-O-galactoside, QUE-3-O-rhamnoside, and QUE-3-O-rutinoside [14]. The amount of QUE contained in selected foods is presented in Table 1, and the chemical structure of QUE is illustrated in Figure 1.
Chemical structure of quercetin and its metabolites.
In contrast to naturally occurring QUE, mainly in the form of glycoside, dietary supplements in the marketplace containing QUE are provided as a free form of quercetin the aglycone [14]. Pharmacologically, QUE has been evaluated for its antiviral and antibacterial activity, anti-inflammatory effects, antiplatelets, antihypertensive, antitumor, neuroprotective effect, cardioprotective effect, gastroprotective effect, natural antihistamine, hepatoprotective, and antiprotozoal [12, 13, 16]. In Western diets, intake of QUE is between 3 and 40 mg per day as aglycones equivalent. In “high-end fruits and vegetables consumers,” the intake has been estimated equal to 250 mg per day [14]. Intended daily doses of QUE as a dietary supplement are often considerably higher than QUE levels taken from natural dietary products (i.e., fruits and vegetables). Most commonly, the recommended daily dose of QUE as a form of dietary supplement (QUE aglycone) is equal to 500 mg (maximum dose is 1000 mg) [14]. Some manufacturers in some countries recommend daily doses of 200 to 1200 mg QUE [17].
Identification of different QUE in any food is possible with different types of chromatography; some of these bioassays are an excellent choice for the quantitative and qualitative analysis of various metabolites. By these methods, a group of scientists has successfully shown the extraction of QUE and other flavonoids in the mulberry leaf, apples, and onions, which are the potential sources of QUE [18, 19].
Most of the QUE in food plants is bound to a sugar molecule via a beta-glycosidic link (also known as glycosyl group), and this conjugation is called glycoside. The factors that mainly affect QUE absorption include the nature of the attached sugar and the solubility as modified by ethanol, fat, and emulsifiers [20]. Sugar molecules are released from the glycosides after mastication, digestion, and absorption [13]. Prior to absorption, QUE glycosides (QUE glucoside, QUE arabinoside, and QUE galactoside) are deglycosylated to QUE aglycone by lactase phlorizin hydrolase (LPH) and cytosolic β-glycosidases (CBG) in the enterocytes brush border [21, 22]. The deglycosylation of QUE glycosides possesses an essential role in increasing its absorption in the intestine, increasing its plasma concentration, and improving its bioavailability [23]. It is established that QUE aglycones are more readily absorbed due to their relatively higher lipophilicity in contrast to their glycoside counterparts, where the absorption in vivo is significant through passive diffusion (Figure 2) [24, 25].
Figure 2.
Processing of quercetin glycosides in small intestine and large intestine. 3-HPAA, 3-hydroxyphenylacetic acid; CBG, β-cytosolic glucosidases; DOPAC, 3,4-dihydroxyphenylacetic acid; Glu, glucuronide; LPH, lactase-phlorizin hydrolase; MCT, monocarboxylate transporter; MRP2, multiresistance protein 2; QUE, quercetin; and UGT, uridine-5′-diphosphate glucuronosyl transferases.
As LPH works directly on the intestinal lumen by cleaving polar glycosides, the released aglycones are then able to passively diffuse across the intestinal wall [22]. However, LPH is not evenly distributed and expressed along the gastrointestinal tracks (GIT) of mammals, mainly because of region specificity and the postweaning decline. Considering that the enzyme in the enterocytes brush border is specific for glucose, QUE glucosides are absorbed more quickly than other glycosides, such as rutin (QUE-3-O-rutinoside) [26]. Rutin (QUE-3-O-rutinose) is neither the substrate of LPH nor CBG, which is hardly absorbed in the small intestine and delivered to the distal part of the GIT, where it is absorbed following degradation by colonic microbiota [27]. Fascinatingly, in the lower gut, the deglycosylation of rutin (QUE-3-O-rutinoside) is mediated by CBG secreted by the gut microbiota or microbial hydrolases (by α-rhamnosidase and β-glucosidase) instead of that by the colonic epithelium since LPH and CBG expression in the latter is insignificant and low [28]. Hence, the absorption rate and efficiency of rutin are considerably less in contrast to other glycosides [29, 30]. In light of this, an in vitro study revealed that approximately 60% of QUE rutinoside were degraded to 3,4-dihydroxyphenylacetic acid within 2 hours by the microbiota in the colon, proposing that most QUE rutinoside is initially deglycosylated to QUE aglycone before its degradation to 3,4-dihydroxyphenylacetic acid and 3-hydroxyphenylacetic acid [20].
Moreover, QUE-3-glucoside and rutin have been detected in the basolateral membrane monolayer in vitro, detected and identified in plasma in in-vivo studies. Some studies also reported that all forms of polyphenols, including intact aglycones, the original glycosides, and the metabolites, coexist in fecal samples in the colon [28]. Therefore, the absorption mechanism in the gastrointestinal tract, especially quercetin, must be revisited.
3.2 Specific membrane transporter mediates QUE absorption
QUE conjugates are challenging to pass via cellular membrane because a lipid bilayer with high membrane polarity requires a specific transporter to cross the membrane. QUE is relatively lipophilic with low solubility in the water. However, QUE glucoside is more water soluble than the aglycone [21]. Additionally, QUE glucoside is absorbed via sodium-dependent glucose transporter-1 (SGLT-1) but not with QUE aglycone. Hence, SGLT-1-mediated absorption contributes to a tremendous amount of the glucoside absorption [21, 31]. Glucose transporter 2 (GLUT-2) also plays a role [31]. The pathway and site of QUE absorption rely on its chemical structure. Preclinical studies hypothesize that the glucose moiety utilizes a transporter to aid its absorption across the intestinal lumen. Previous studies using rat models demonstrated that QUE aglycone is absorbed both in the stomach and the intestine, but the absorption mechanism in the stomach remains unclear.
Regarding the absorption in the intestine, some studies utilizing the caco-2 cell monolayer revealed that QUE aglycone is absorbed primarily by passive diffusion and secondarily by organic anion-transporting polypeptides (OATPs) [21, 32]. When flavonols are present in the dietary form of aglycone, they could be partially absorbed in the stomach relative to their glycoside forms, which are not absorbed. The absorption of QUE by these two mechanisms is pH dependent, in which in lower pH, QUE exerts a high affinity as a substrate of OATP-B uptaken into enterocytes via the OATP-B transporter. While in higher pH, QUE is absorbed through a passive diffusion mechanism [32].
3.3 Factors influencing quercetin absorption
The absorption of QUE, such as other flavonoids, is considered poor, resulting in its variably limited bioavailability [29]. QUE absorption is influenced by various factors, including its glycosylation, preparation, coadministration of dietary components along with QUE, and interindividual variability [26, 33]. Preclinical studies demonstrated that QUE glucoside had a greater bioavailability compared to aglycone, presumably due to differences in absorption properties [33]. In particular, QUE glucosides are biochemically more hydrophilic than aglycones. Specific transporters also exclusively facilitate QUE glucoside absorption, including SGLT-1, which contributes to higher intestinal uptake of glucosides (Figure 2) [33, 34]. The sugar moiety in the glucosides also enhances its solubility to aid in absorption. Similar studies conducted in healthy subjects with ileostomy (to avoid the role of losses by colonic bacteria) demonstrated higher absorption in glucosides from onions than pure aglycone (52 ± 15 vs. 24 ± 9%) [35]. QUE bioavailability is also better when prepared in cereal bars than in capsule forms due to the homogenous solid dispersion of QUE with other components in the cereal, promoting dissolution in the intestinal lumen [36].
Co-ingestion of QUE with other dietary nutrients also affects its absorption. Dietary fat enhanced proved the absorption of QUE in a randomized crossover study among overweight/obese and menopausal subjects, improving its plasma maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC) over the 24 hours by 45 and 32% compared to fat-free subjects, respectively. Dietary fats may enhance QUE absorption by micellization in small intestines [37]. Coadministration of QUE with fructooligosaccharides (found naturally in various plants) also increases its bioavailability in preclinical studies [38]. Piperine (Pip), a compound responsible for the pungency of black pepper, is also known to enhance QUE absorption and bioavailability. It improves GIT absorption via multiple mechanisms, including augmenting compound solubility, increasing epithelial cell permeability, and increasing intestinal blood supply. It is also a potent inhibitor of drug hepatic metabolism, thus enhancing QUE bioavailability [39]. A study examining the effect of adding pip in QUE-loaded nanosuspensions demonstrated significantly greater absolute oral bioavailability (23.58% pip-containing nanosuspensions vs. 3.61–15.55% in other formulations) [40]. Vitamin C may also augment QUE bioavailability [33]. From the absorption point of view, ascorbic acid, especially at a high dose, may increase intestinal permeability and stability of QUE molecules to become more soluble in the GIT [41]. However, the evidence demonstrating this effect in humans is lacking. Similarly, QUE coadministration with bromelain, a crude pineapple extract, also enhanced QUE’s oral bioavailability by up to 80% [42].
On the other hand, some dietary companions may decrease QUE bioavailability. For instance, iron, especially nonheme iron in plant-based foods and various supplements, can bind to QUE and reduce absorption. Similarly, QUE and other flavonoids also significantly mitigate iron absorption due to the inhibition of basolateral transport across intestinal epithelial cells [43]. Calcium supplements may also interfere with QUE absorption despite scarce evidence. The mechanism underlying its inhibitory effects is theoretical because calcium can form insoluble complexes with QUE in the GIT, thus reducing its bioavailability. Certain medications may interfere with the absorption and bioavailability of QUE and will be further discussed in the subsequent section (see Section 6. Drug Interactions of Quercetin).
Bioavailability refers to a ratio between the amount of orally ingested substance and the amount that is absorbed and completely available to its intended biological destinations and to exert physiologic activity or storage [44]. For polyphenols, this is often deemed as the amount detected in plasma. The minimum bioavailability can also be calculated as a percentage based on the urinary measurement of the compound and its metabolites [26]. Generally, bioavailability is calculated by measuring QUE derivatives or catabolites in blood or urine [26]. Given that QUE is primarily detected in several conjugated forms in vivo, the analytical procedures followed by most authors are animal and human studies. It is shown that QUE had poor oral bioavailability after a single oral dose, presumably due to variability in the absorption rates related to polymorphism of intestinal enzymes and transporters [45]. The bioavailability of QUE is associated with its bioaccessibility and, thus, solubility in the vehicle for administration. Crystalline formation at body temperature and the poor solubility of QUE restrict its bioavailability and bioaccessibility [21]. Likewise, QUE glycosides or aglycone are effluxed back across the apical membrane into the intestinal lumen following its enterocyte uptake [46]. Data on the bioavailability of QUE (glycoside and aglycone) differ substantially between studies depending on the methods used for measuring QUE level. It also varies between each species. For instance, in human studies, interindividual variations could be influenced by the complexity of QUE absorption and metabolism, dietary adaptation, genetic polymorphism, body mass index (BMI), the composition of gut microflora, and drug-drug interactions [26]. The bioavailability of QUE can be improved by ingestion with short-chain fructooligosaccharide (FOS) or form of cereal bar ingredient rather than in capsule form [21]. Co-ingestion with dietary lipids increases the intestinal absorption of quercetin. A previous clinical study by Guo et al. suggested that individual differences in the level of plasma vitamin C may contribute to intersubject variability in the bioavailability of QUE [47]. Additionally, some in vitro studies revealed that the presence of vitamin C can protect QUE against oxidative degradation [34], yet further studies are required regarding the role of vitamin C in regulating the bioavailability of quercetin.
In one clinical study, 35 healthy subjects were randomly assigned to take a designated dose of QUE capsules of either 50, 100, or 150 mg daily for 2 weeks. The supplementation significantly raised plasma levels of QUE by 178, 359, and 570% for each dose of 50, 100, and 150 mg, respectively, compared to baseline status. The AUC was between 76.1 and 305.8 mmol/min/L (50- and 150-mg dosages, respectively). The achieved median maximum plasma level was approximately 431 nmol/L after 360 minutes of ingesting 150 mg of quercetin. Based on this study, daily supplementation of QUE for 2 weeks dose-dependently raised plasma levels of QUE without affecting antioxidant status, inflammation, metabolism, and oxidized LDL [17]. Another larger randomized placebo-controlled trial involving 1002 healthy subjects showed that QUE supplementation in doses of 500 and 1000 mg per day significantly raised plasma levels of QUE but was highly variable after continuous administration over 12 weeks. However, the variability was unrelated to the age, gender, BMI, and lifestyle factors of the subjects [45].
In clinical studies, the extent of QUE absorption can be estimated by multiplying the Cmax by plasma volume (on average 3.5 L in a normal 70-kg adult) and dividing by the administered dose of quercetin. Likewise, scanty amounts of QUE aglycone were detected in plasma compared to QUE conjugates (glycoside), which could be recovered in plasma after oral ingestion [14]. The pharmacokinetics of intravenous QUE in cancer patients were studied by Ferry et al. at dose levels of 60–2000 mg/m2 [48]. It was concluded in this study that 945 mg/m2 was the safe intravenous dose of quercetin. In the same survey, a toxic amount was reported to induce emesis, hypertension, nephrotoxicity, and decreased serum potassium. Ferry et al. further concluded that the distribution and elimination half-life (t½) of intravenous QUE was 0.7–7.8 and 3.8–86 min, respectively, and its clearance and distribution volume was 0.23–0.84 and 3.7 L/m2, respectively [29, 30, 48].
Recently, hepatic transport processes have been recognized as an essential determinant of drug disposition. Therefore, unsurprisingly, the characterization of potential drug candidates’ hepatic transport and biliary excretion properties is necessary for the drug development process [49]. Basolateral transport systems are responsible for translocating molecules across the sinusoidal membrane. Conversely, active canalicular transport systems are responsible for the biliary excretion of drugs and metabolites [50]. Numerous transport proteins involved in basolateral and canalicular transport have been identified. QUE has been proven to be the substrate of OATP2B1, OATP1A2, and organic cation transporter-1 (OCT1) in the OATPs-HEK293 cell line. In addition to passive diffusion, OATP2B1, OATP1A2, and OCT1 may also arbitrate QUE transport and contribute to QUE accumulation in hepatocytes [51]. Moreover, OAT4 on the basolateral membrane of hepatocytes confers an essential role in the cellular uptake of QUE-3′-sulfate [52]. On the one hand, the primary intestinal metabolites of quercetin, QUE glucuronides, may be transported primarily by passive diffusion [53].
QUE metabolism occurs mainly in the gastrointestinal tract. In mouse models, approximately 93% of QUE aglycone, or the one from hydrolyzed derivatives, is metabolized in the intestine after absorption. Albeit most QUE is metabolized in the small intestine, the liver contains all the enzymatic systems that allow its complete metabolism through reactions of methylation, sulfation, and glucuronide conjugation. Efficient glucuronidation of QUE takes place in enterocytes by UDP-glucuronyltransferases (UGT), methylation by catechol-O-methyltransferases (COMT), and sulfation by sulfotransferases (SULT) [54]. In an attempt to migrate from the cell to the bloodstream, conjugation has to occur, and conjugated QUE metabolites are formed. Consequently, QUE aglycone is present in low amounts in plasma. The two principal metabolites in humans that pass into the blood from the enterocyte are QUE-3-O-glucuronide and QUE 3′-O-sulfate, which are transported from the enterocyte to the liver via the portal vein [55, 56].
QUE and its metabolites will undergo phases I and II metabolism while reaching the liver, similar to other flavonoids. Phase I metabolism mainly includes oxidation, reduction, and hydrolysis by facilitating its subsequent metabolism by introducing a physiological functional group. Hence, it can increase the reactivity of the substrate. Phase I metabolism is mediated by cytochrome (CYP) 450 (CYP450) and has minimal effect on overall flavonoid metabolism [57]. However, QUE can affect the substrate bioavailability of CYPs by activating or inhibiting CYP activity. QUE has been identified as a competitive inhibitor of CYP2C19, CYP3A4, and CYP2D6 in human liver microsomes model [58].
QUE and its metabolites undergo further phase II metabolism in the liver following specific pathways: glucuronidation, sulfation, and methylation. These pathways facilitate the excretion of QUE and its metabolites through bile and urine [59]. Glucuronide conjugates are the primary existing forms of QUE in the bloodstream. UGTs promote the conversion of hydrophobic substrates to hydrophilic glucuronides, which are vital in reducing the bioactivities of xenobiotics [60]. Sulfation has the primary role of reducing potential toxicity by adding sulfate groups to xenobiotics. The 3′-OH is reckoned to be an essential site for the sulfation of quercetin. COMT mediates the methylation of QUE at 3′-OH or 4′-OH of catechol to generate 3′O-methylquercetin and 4′OH-methylquercetin [48], respectively. Glucuronide derivatives are the primary metabolites of QUE in the intestine and liver. QUE-3′-sulfate was also found as another significant metabolite. The generation of QUE sulfate conjugate shows that QUE glucuronide conjugates can still be mediated by β-glucuronidase in the liver to generate QUE aglycone. SULT then metabolizes QUE aglycone to form the corresponding sulfate [61].
Following metabolism in the liver, the QUE metabolites are secreted into bile and appear in the feces. Approximately 35% of QUE metabolites were observed in bile, and metabolites resulting from glucuronidation and sulfation were the predominant existing forms [62]. As seen in Figure 3, QUE phase II metabolites are the substrates of breast cancer resistance protein (BCRP) and multiresistance protein 2 (MRP2) efflux transporter. Specifically, MRP2, located on the apical membrane of hepatocytes, facilitates the secretion of QUE glucuronide and QUE 3′-O-sulfate into bile, leading to a lower bioavailability of QUE metabolites [61]. Synchronously, QUE glucuronide and sulfate conjugates secreted into bile and reaching the intestine may then be reabsorbed and thus enter the portal vein circulation [63]. Nevertheless, no significant absorption of QUE and its conjugates was identified in mouse models by intravenous injection of QUE and its bile into the duodenum, denoting QUE metabolites that do not possess enterohepatic circulation [64]. Hence, we require further studies to understand whether enterohepatic circulation can improve the bioavailability of quercetin.
Figure 3.
The process of metabolism and transport of QUE and its metabolites in the liver. COMTs, catechol-O-methyltransferases; Glu, glucuronide; MQUE, methyl quercetin; MRP2, multi-resistance protein 2; OATPs, organic anion transport polypeptides; OCT, organic cation transporter; QUE, quercetin; SULT, sulfotransferases; UGTs, uridine-5′-diphosphate glucuronosyl transferases.
Additionally, phase II conjugates of QUE in the liver may also be transported to the circulation through MRPs located on the basolateral membrane of hepatocytes [65]. QUE-3-O-glucuronide, 3′-methylquercetin-3-O-glucuronide, and QUE 3′-O-sulfate are the main existing forms of QUE in human plasma after oral onions. In plasma, QUE metabolites bind to albumin primarily via non-covalent bonding, and the binding ratio is approximately 70–80% distinct in the antioxidant activity between various QUE conjugates [66]. Contrary to QUE aglycone, the biological activity of phase II conjugates is reduced, such as methylated QUE with reduced antioxidant activity [67].
A crossover clinical study demonstrated that single-dose and repeated intake (short-term) of QUE (1500 mg/day) decreased the Cmax and AUC0-∞ values of talinolol (substrate of intestinal P-glycoprotein) in human volunteers. The authors suggested that this occurs due to interaction between quercetin, P-glycoprotein (efflux), and OATP (uptake) transporters, predominantly by inhibition of talinolol absorption mediated by OATP [68].
Pharmacokinetic interactions of QUE aglycone and its primary metabolites with the albumin binding of warfarin were also evaluated in vitro. A study by Poor et al. [69] showed that QUE metabolites exhibited high affinity binding to human serum albumin, and the methylated and sulfated metabolites had similar or even greater abilities to displace warfarin binding to albumin than the parent compound. On the other hand, the glucuronide conjugates exhibited lower affinity binding to human serum albumin; thus, the competition with warfarin was also lower. The researchers suggested that repeated exposure to large doses of QUE renders significant interaction with warfarin since the displacement of warfarin from human serum albumin leads to bleeding, and subsequent serious effects may follow. However, the study showed that QUE and its metabolites exerted a considerably lower impact on hydroxylation catalyzed by CYP2C9 than warfarin [69].
Contrariwise, a randomized, open-label crossover study by Nguyen et al. [70] demonstrated that a single oral dose of 1500 mg QUE did not alter midazolam pharmacokinetics significantly, while one-week supplementation of QUE rendered a trend to decreased midazolam exposure and reduced the ratio of midazolam - 1′-hydroxymidazolam AUC0-∞. It indicated that QUE induced a CYP3A4 activity. Likewise, the coadministration of QUE and midazolam would not trigger any toxic adverse effects. However, the therapeutic efficacy of midazolam may be reduced when administered orally following a short-term high-dose QUE supplementation, presumably due to elevated CYP3A4-mediated metabolism of the drug [70]. Another crossover study demonstrated that concomitant short-term intake of QUE (500 mg three times a day for 1 week) significantly increased the mean plasma concentration of fexofenadine compared to those of the placebo phase. However, there was a significant decrease of 37% in oral clearance of fexofenadine after QUE intake. There was no difference in the t½ and renal clearance between the QUE and placebo phases. It was suggested that inhibition of p-glycoprotein-mediated efflux was involved in this process [71].
Individuals on therapeutic regimens with narrow therapeutic windows should be under physician supervision before use. It has been shown that QUE enhances antifungals and antibiotics, particularly those targeting the fluconazole-resistant group of Candida albicans [72] and Candida tropicalis [73], multidrug-resistant Pseudomonas aeruginosa [74], amoxicillin-resistant Staphylococcus epidermidis [75], and multidrug-resistant Escherichia coli [76]. It also competitively inhibits bacterial DNA gyrase; hence, it is contraindicated to concomitant use with fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin) [77].
Apart from the transport and excretion of the metabolized QUE in its glucuronidated, methylated, and sulfated forms into the bile (Figure 3), a considerable amount of its metabolites are transported via the bloodstream into the kidneys. Furthermore, in addition to exerting its renoprotective effects (e.g., antioxidant, anti-inflammatory, anti-fibrotic), kidneys would also transport the metabolites into the renal cells and renal tubules for excretion. Some hydrophilic metabolites from the bloodstream may go through glomerular filtration, while others are secreted into the tubule, mainly in the proximal convoluted tubule (PCT) [54, 78].
The transport of QUE to PCT epithelial cells principally occurs in the basolateral membrane (BLM) and brush border membrane (BBM) [79]. OATs are abundantly expressed on the BLM of the PCT epithelial cells to facilitate the transport. Significantly, QUE 3′-O-sulfate and QUE 3′-O-glucuronide are actively transported into the PCT cells owing to high affinity for OAT1 and OAT3, respectively (Figure 4) [46]. Contrarily, QUE 3-O-glucuronide and QUE 7-O-glucuronide have poor affinity for OAT1 and OAT3. On the side of BBM of PCT epithelial cells, MRP2 and BCRP are the primary transporters responsible for the secretion of glucuronidated QUE, whereas its sulfated metabolites are transported via MRP2 [46, 61].
Figure 4.
Schematic illustration of the transport and excretion of quercetin by the kidney. BCRP, breast cancer receptor protein; BLM, basolateral membrane; BMM, brush border membrane; Glu, glucuronide; MQUE, methyl-quercetin; MRP2, multi-resistance protein 2; OAT, organic anion transporter; OATP, organic anion transport polypeptide; PCT, proximal convoluted tubule; and QUE, quercetin.
QUE and its metabolites are also partially reabsorbed into the tubular cells [78]. QUE aglycone and methyl-quercetin can be passively reabsorbed into the tubular cells across the BBM, whereas its sulfated and glucuronidated conjugates necessitate active transporters for reabsorption. The passive influx of aglycone across BBM is thought to be due to its lipophilic properties, whereas methylated conjugates can be passively reabsorbed owing to their planar configuration. On the other hand, most hydrophilic metabolites are less likely to be reabsorbed under physiological circumstances. However, some transporters for active reabsorption have been identified and may play a role in active transport across BBM, which include organic anion transporter 4 (OAT4) for sulfated conjugates and MRP2 and BRCP for glucuronides [80].
Mullen et al. examined the excreted metabolites of QUE after ingesting lightly fried onions in healthy human subjects. They concluded that the proportion of QUE metabolites being excreted in the urine from the dietary intake of QUE is around 4.7% of the total intake (12.9 μmol) [81]. In addition, the profile of metabolites excreted in urine differed significantly from that of plasma, with twelve urinary metabolites being detected in the study [54, 81]. QUE diglucuronides contributed to most of the QUE metabolites in the urine, while other substantial metabolites include QUE 3′-glucuronide, isorhamnetin-3-glucuronide, and QUE glucuronide sulfates (Table 2) [81]. Mullen et al. stipulated that the most probable fate of the majority of non-excreted metabolites is the conversion to various phenolic acid compounds, most likely 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylpropionic acid, and 3-methoxy-4-hydroyphenylpropionic acid, which were not measured in the study [81, 82].
Metabolites
24-h Urinary Excretion
Mean (nmol)
% of total excreted metabolites
QUE Diglucuronide
2223
21%
QUE-3’-Glu
1845
18%
I-3-Glu
1739
17%
QUE Glu Sulfate
1384
13%
MQUE Diglucuronide
1003
10%
QUE-3-Glu
912
9%
I-4′-Glu
700
7%
QUE Glucoside Sulfate
392
4%
QUE Glu Glucoside
163
2%
Total
10,361
100%
Table 2.
Mean and percentage of quercetin metabolites detected in urine at 24 hours, adapted and modified from Mullen et al. [81].
QUE, quercetin; Glu, glucuronide; nmol, nanomole; and MQUE, methylquercetin.
There is a considerably large interindividual variation in QUE excretion. Ferry et al. examined 51 cancer patients in a phase I clinical trial of quercetin, in which the subjects were administered by a short IV infusion at doses of 60 to 2000 mg/m2 of QUE aglycone. They reported the proportion of the excreted QUE in urine over 24 hours ranged between 0.03–7.6%, implying variability between subjects [48]. Various studies also examined the t½ of QUE with variable conclusions. Some studies examining the half-life of orally administered QUE reported a t½ ranging between 11 and 28 hours [27, 81, 82, 83]. On the other hand, two studies evaluating the pharmacokinetics of IV QUE aglycone concluded the t½ of 0.7–2.4 hours [48, 84]. There was consistently significant clearance at 24 hours, and the elimination of QUE was completed within 48 hours of ingestion. Renal clearance after ingestion of 100–200 mg of various QUE glycosides was estimated to be 0.7 L/h. In contrast, Moon et al. reported that renal clearance of 500 mg of QUE aglycone after ingestion was significantly higher, approximately 3.5 × 104 L/h [3, 29]. The urinary recovery, the proportion of excreted drugs through the urine unchanged, was estimated to be 1.0 ± 0.8%.
Tubular cells, in addition to their efflux and influx properties across different membranes, also act as metabolic machinery for QUE in the kidney. The biochemical conversion includes various deconjugation processes of various metabolites to yield aglycones (e.g., deglucuronidation by β-glucuronidase), followed by instantaneous glycosylation by β-glycosyltransferase, sulfation by SULTs, glucuronidation by UGTs, and methylation by COMTs [54].
QUE is abundant in the human diet and has potential benefits for human health. Dietary supplement of QUE is available over the counter as a free form of QUE aglycone. In contrast to naturally occurring QUE contained in fruits and vegetables, the intended daily doses of QUE supplements are considerably higher, ranging from 500 to 1000 mg. The majority of the absorption of QUE occurs in the small intestine, and insignificant portions are absorbed in both in the stomach and colon. In the intestine, the aglycone is primarily absorbed via a passive diffusion mechanism and secondarily via OATP, whereas the glucosides are achieved via specific transporters. Following the absorption in the enterocytes, QUE undergoes extensive metabolism in the liver, resulting in sulfated, glucuronidated, and/or methylated metabolites.
Based on the pharmacokinetics profile, QUE has poor oral bioavailability after a single oral dose. The bioavailability of QUE is associated with various factors, including its solubility and coadministration of other dietary components. Hence, its formulation to improve absorption rates and reach its optimum plasma level should be considered important. The effects of coadministration of other dietary supplements, such as vitamin C and bromelain, should further be investigated in future clinical studies. It must also be taken into consideration that QUE and its metabolites may interfere with the pharmacokinetics of some drugs by variably interacting with various CYP enzymes; they also inhibit multispecific OATP, ABC, and transporters at micromolar levels.
This article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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Written By
Muhammad Candragupta Jihwaprani, Wahyu Choirur Rizky and Mazhar Mushtaq
Submitted: 20 September 2023Reviewed: 21 September 2023Published: 18 December 2023
Open access peer-reviewed chapter - ONLINE FIRST
