Quercetin as Natural Bioavailability Modulator: An Overview
Rachana Bhimanwar*, Lata Kothapalli, Akshay Khawshi
Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune
*Corresponding Author E-mail: r.09joshi@gmail.com
ABSTRACT:
India is a country with variety of the medicinal herbs. Quest for safer and natural opinion for treatment of diseases led about 80% of world population to rely on herbal medicine .In advance drug design technology, a large number of drug molecules are being introduced every year but many have bioavailability issues with long lasting side effects. Low bioavailability leads to alteration in therapeutics efficacy of medicaments and cause hindrance encountered during new drug or drug product development .Thus there is need of molecules which when combine with other drugs enhance their bioavailability. Bioenhancers are such agents which by them when combined with active drugs lead to potentiation of pharmacological effect of drug by increasing bioavailability. Natural bioenhancers are the plant based molecules which promote biological activity or uptake of the drugs alone or in combination therapy. Along with piperine as Bioenhancer, proven in many cases there are many other natural constituent which possess Bioenhancer property. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. This article reviewed and emphasizes on the biopotentiator property of Quercetin.Quercetin is a plant pigment (flavonoid), found in many plants and foods, such as onions, green tea, apples and others. Buckwheat tea has a large amount of quercetin. Quercetin also has a as a medicinal benefits.
KEYWORDS: Bioenhancer, Quercetin, Bioavailability enhancement.
INTRODUCTION:
Now a day’s plant based medicines widely used all over the world. Our ayurveda have mention a thousand of herbal drugs and extract for the various diseases and rare disease also. Modern pharmacopeia also contains 25-30% of drugs from plant origin. Ayurveda also made a major contribution in the drug discovery process in pharmacology.
Many diseases like viral, Cancer, cardiovascular, diabetes etc. require long term therapy and patients are continuously exposed to medicaments. About 90% of the drugs have poor bioavailability and solubility because of that the drug is less bioavailable in the systemic circulation. Then such poorly bioavailable drugs required high dose, which then result in severe adverse effect, drug resistance, and increase in the cost.
Many synthetic and herbal drugs have less aqueous solubility because of which it has less bioavailability, poor dissolution and poor membrane permeability. Maximum bioavailability is attained by drug administered by intravenous route. Whereas drug which are administered orally has poor bioavailability as they undergo first pass metabolism and incomplete absorption. Such unutilized drug may produce adverse effect and drug resistance in body. Incomplete oral bioavailability has various causes. These include poor-dissolution or low aqueous solubility, poor intestinal membrane permeation, degradation of the drug in gastric or intestinal fluids and presystemic intestinal or hepatic metabolism1
Bioavailability is a rate and extent to which substance enters into systemic circulation and becomes available at the site of action. Thus used of bio enhancers seem to be fruitful method for increasing bioavailability. There is need of entity which they do not produce any therapeutic effect but when they co-administered with other drug/molecule enhance their bioavailability 2. Thus bioenhancers are chemical entities which enhance the bioavailability of other drug and not produce any synergistic or antagonistic action.
HISTORY:
Now a days, bioavailability enhancers or natural bioavailability modulators is a concept in medical science first scientifically established in 1979 after the discovery of world's first bioenhancer Piperine. It is a eco-friendly drug technology which reduces the dose dumping, dose duration and various side effects of several orally administered drugs inside the body.
The term ‘Bioavailability modulator’ first invented by Indian Scientist at Regional Research Laboratory (RRL), Jammu. Piperine is world’s first Bioavailability enhancer, which is Discovered, Scientifically Approved and Validated by RRL.
Apart from Piperine, which has the honour to be first bioenhancer, many other natural active constituents also possessed bioenhancement capability. Every bioenhancers have specific properties. Some may have similarities and differences in increaseing the bioavailability of different drugs by using different mechanism of action.
DIFFERENT METHODS FOR BIOAVAILABILITY ENHANCEMENT:
Natural Bioenhancers:
The bioavailability enhancer from natural origin are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Though the concept of bioenhancers are innovative for enhancing the bioavailability of several potent drugs, there are many bioenhancers of herbal origin that are yet to be explored and properly studied in several vital areas of medical science. All studies so far emphasized on enhancement of bioavailability through oral route, so, other routes of drug delivery are to be explored for enhancement of bioefficiency of potent drugs.
There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response.
Bioenhancers from herbal origin:
Piperine, Quercetin, Curcumin, Ginger, Indian Aloe Leaves, Allicin, Caraway, Glycyrrhizin, Sinomenine, Gallic acid, Drumstick pods, Tea.
Bioenhancers from non-herbal origin (from animal sources):
Cow urine distillate, Campul.
Bioenhancers have some inert properties such as:
· Nontoxic to human or animals.
· It should be very effective when given in combination.
· It should be increase the uptake/absorption of other drug.
· It should be readily compatable and easy to formulate.3
ADVANTAGES OF BIOENHANCER4
There are various advantages using bioenhancer in the combination therapy. These are following
· Efficacy of drug is increase due to increase in bioavailability.
· Combination of bioenhancer with drug reduces the dosage and dangers of drug resistance can be minimized.
· Reducing the dose can decrease the cost factor also, make the treatment economical
· Adverse drug reaction/side effect and toxicity of drug will be minimized because of reduced dosage.
· There are ecological benefits too eg. Toxol used to treat ovarian cancer or breast cancer is derived from bark of Pacific yew tree, one of the slowest growing trees in the world. At present to treat one patient, six trees, 25-100 years old need to be felled with bioenhancers fewer trees will be destroyed.
COMMON MECHANISM ACTION OF NATURAL BIOENHANCERS5-6:
1. Alteration in the activity of enzymatic system.
(Suppresed CYP-450 enzymes and P-Glycoproteins):
Bioenhancers inhibite CYP-450 enzyme and its isoenzymes i.e. CYP3A4 enzymes and other such as CYP1A1, CYP1B1, CYP1B2, CYP2E1 are inhibited or induced by bioenhancers.
Efflux transporter play an important role in drug transporting in many organs.In gastrointestinal tract, P-glycoprotein pumps decrease the rate of drug by taking back it into lumen.
Example-Caraway, Genistein, Sinomenine.
2. Regulation of GIT to facilitate better absorption:
Bioenhancers increase the drug absorption via paracellular route by redistribution of the cytoskeletal. It also increase the solubility of hydrophobic drugs in the aqueous layer and increase the fluidity of apical and basolateral membranes.
Example – Aloe, Niaziridin (Drum stick),Zingiber officinale, Glycerrizin.
3. Cholagogous effect (Promote discharge of bile):
Bioenhancers promote the flow of bile into the intestine by the contraction of the gallbladder.
4. Thermogenic properties:
Bioenhancers having thermogenic property, which increase the rate of metabolism by increasing the temperature. By this way bioenhancers improve the gastric mobility and decrease the absorption of cholesterol.
5. Stimulation of gamma glutamyl transpeptidase activity (GGT):
GGT is a membrane bound glycoprotein which located on the outer surface of the cell membrane and used as biomarker for the liver, biliary system and pancreatic diseases.
6. Alteration of gastrointestinal transit and intestinal motility:
Saponin containing bioenhancers increase the permeability of intestinal mucosal cells and inhibite active mucosal transport. This facilitates uptake of those substances that are normally not absorbed.
Eg. Essential oils obtained from cuminum cyminium, Carum carvi, Zingiber officinale etc.
QUERCETIN AS BIOENHANCER:
Quercetin, a plant-derived aglycone form of flavonoid glycosides, has been used as a nutritional supplement and may be beneficial against a variety of diseases. Some of the beneficial effects include cardiovascular protection, anticancer, antitumor, anti-ulcer, anti-allergy, anti-viral, anti-inflammatory activity 7anti-diabetic8-11, gastroprotective effects12, antihypertensive13,14, immunomodulatory, and anti-infective.15
Quercetin might help lower inflammation, fight allergies, support heart health, combat pain, potentially improve endurance, fight cancer, and protect skin and liver health.
Some of the top sources include apples, peppers, red wine, dark cherries, tomatoes, cruciferous and leafy green veggies, citrus fruits, whole grains, legumes, herbs, and more.
Source
|
Sources |
Content (mg/kg) |
|
Black and Green Tea |
2000-2500 |
|
Apples |
44 |
|
Capers |
1800 |
|
Onion (Red Onion) |
1910 |
|
Red grapes, citrus fruit, tomato, broccolli, other leafy green vegetables |
158 |
|
Cranberry |
83 |
|
Rowanberry |
63 |
|
Sweet Roman |
85 |
PHARMACOKINETICS OF QUERCETIN IN RAT:
Quercetin is present in many fruits and green vegetables. The bioavailability of quercetin in humans is low and highly variable (0–50%), and it is rapidly cleared with an elimination half-life of 1–2 hours after ingesting quercetin foods or supplements., quercetin undergoes rapid and extensive metabolism that makes the biological effects presumed from in vitro studies unlikely to apply in vivo.16-18
In rats, quercetin not undergo any significant phase I metabolism. In contrast, quercetin undergo extensive phase II (conjugation) to produce metabolites that are more polar than the parent substance and hence are more rapidly excreted from the body. The meta-hydroxyl group of catechol is methylated by catechol-O-methyltransferase. Four of the five hydroxyl groups of quercetin are glucuronidated by UDP-glucuronosyl transferase.
The exception is the 5-hydroxyl group of the flavonoid ring which generally does not undergo glucuronidation. The major metabolites of orally absorbed quercetin are quercetin-3-glucuronide, 3'-methylquercetin-3 glucuronide, and quercetin-3'-sulfate.
ISOLATION AND EXTRACTION OF QUERCETIN FROM ONION SCALE:
Extraction Methods:
There are many methods for extraction of quercetin.
1. Supercritical water extraction.
2. Ultrasound assisted extraction.
3. Extraction by Labortary Method.
Extraction by Laboratory Method19:
Maceration, infusion and Soxhlet extraction are the conventional methods used for the extraction of photochemical from plants which are included in Solid-liquid extraction methods. These extraction processes involve following steps.
1. The diffusion of the solvent into the plants cells,
2. solubilisation of the phytochemical compounds within the plant matrix
3. Diffusion of the phytochemical-rich solvent out of the plant cells.
Traditional extraction technologies, such as solvent extraction and steam distillation, have been used for the recovery of natural extracts from plant and animal sources for a long time but has various disadvantages like more solvent used, less yield etc and thus modern extraction techniques has been discovered and used.
Supercritical water extraction20,21:
Supercritical fluid extraction (SFE) is the process of separating one component (the extractant) from another (the matrix) using supercritical fluids as the extracting solvent. SFE can be used as a sample preparation step for analytical purposes.
Carbon dioxide (CO2) is the most used supercritical fluid, sometimes ethanol or methanol as co-solvents are also used. Extraction conditions for supercritical carbon dioxide are above the critical temperature of 31°C and critical pressure of 74 bar .
ADVANTAGE:
1. Faster rate : Supercritical fluid Extraction is a diffusion-based process. Diffusivities are much faster in supercritical fluids than in liquids, and therefore extraction can occur faster.
2. More penetration of solvents: the solvent can penetrate more into the matrix inaccessible to liquids due to the lack of surface tension and very less viscosities as compared to liquids,
3. Less Time: An extraction using an organic liquid may take several hours, whereas supercritical fluid extraction can be completed in 10 to 60 minutes.
Procedure: The system contain
· A pump for the CO2,
· A pressure cell to contain the sample, a means of maintaining pressure in the system
· A collecting vessel. The liquid is pumped to a heating zone, where it is heated to supercritical conditions.
Solvent passes into the extraction vessel, where it rapidly diffuses into the solid matrix and dissolves the material to be extracted. The dissolved material is swept from the extraction cell into a separator at lower pressure, and the extracted material settles out. The CO2 can then be cooled, re-compressed and recycled, or discharged to atmosphere.
Ultrasound assisted extraction22,23:
Ultrasound disrupts the cell wall structure and accelerates diffusion through membranes; thus, the cell lyses and hence facilitates the release of cell contents.
Advantage:
The use of ultrasound or sonication to break the cell membranes has the advantage of reducing considerably the extraction time and increasing the extract yield
QUERCETIN AS BIOENHANCER:
Quercetin is a bioflavonoid which is extensively studied by the researchers last from 30 years. Bioflavonoids were first discovered by Albert Szent Gyorgyi in the 1930. He won Nobel prize for it.
Source: fruits, onion, grains, bark roots, stem, flowers, tea and wine. .
It is a dual inhibitor of cytochrome P 3A4 and modulator of P-glycoprotein resulting in the enhanced bioavailability of API.24
MECHANISM OF BIOENHANCING EFFECT OF QUERCETIN:
By action on drug metabolizing enzyme:
One of the reason for bioenhancing effect of quercetin is attributed to the interaction of quercetin with enzymes that participate in drug metabolism, such as mixed function found in the liver and intestinal cells or due to inhibition of hepatic and non hepatic drug metabolizing enzyme. It works by inhibiting CYP3A4 and P-gp efflux pump.25
BIOAVALABILITY ENHANCEMENT OF QUERCETIN:
Quercetin and Berberine:
Sarika Narade et.al. (2019)26 investigated the permeability characteristics of berberine chloride alone and in presence of bioenhancer quercetin on goat intestine using Franz diffusion cell. A 32 full factorial design approach was employed for investigation. The effect of quercetin on permeability of Berberine was examined at three different concentrations (2, 6, and 10 mg) with different levels of pretreatment time (30, 45, and 60 minutes) .Results showed the dose dependent positive effect on % CDR and detrimental effect of increase in pretreatment time by quercetin on % CDR. In vitro anticancer activity of optimized batch demonstrated non-significant effect as compared with parent drug. In conclusion, quercetin could be successfully utilized as bioenhancer to improve ex vivo permeability of berberine chloride, which would be expected to improve its bioavailability and reduce the dose resulting in improved patient compliance.
Quercetin and Curcumin:
Manodeep Chakrabortya, et.al. (2018)27 studied the effect of quercetin on myocardial potency of curcumin against ischemia reperfusion induced myocardial toxicity. Curcumin is cardioprotective in nature but to improve the therapeutic efficacy the bioavailability enhancement is must. The present study includes the use of bioenhancer like Quercetin by combining with Curcumin against ischemia reperfusion injury (IRI) induced myocardial toxicity in rats. Rats were treated orally with CUR alone and combination of CUR and QUE for 30 days. CUR and QUE demonstrated significant myocardial potency compared to CUR alone-treated group. Significant increase in bioavailability and half life, along with significant decrease in clearance was observed for CUR in combination group compared to CUR alone treated group. Influence of QUE on pharmacokinetic of CUR was studied by HPLC method. Results of pharmacokinetic interaction justified the results of pharmacodynamic interaction.
Quercetin and Losartan
Qingling Zhao et. al., (2018)28 investigated the influence of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. The pharmacokinetic profiling of losartan (10 mg/kg) and EXP3174 was done with or without pretreatment with quercetin for 7 days. The results showed that when the rats were pretreated with quercetin, the Cmax and the AUC of losartan increased significantly (p < 0.05), and while the Cmax of EXP3174 decreased significantly. These results indicated that the herb-drug interaction between quercetin and losartan by inhibiting the activity of P-gp and the activity of CYP450 enzyme.
Quercetin and Cefprozil:
Fei-Fei Jia et. al., (2016) 29the objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil and to check safety of the combined use of cefprozil and quercetin. Phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500 mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. They measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects.
Quercetin and Gentamicin:
Pamela Soledad et. al., (2016)30 evaluated the ROS production effect of gentamicin and gentamicin plus quercetin in human leukocytes. Gentamicin generated ROS production in human leukocytes, produced a dual effect on both enzymes dosage-dependent and generated an increase in lipid peroxidation. It was concluded that gentamicin could induce oxidative stress in human leukocytes and in whole blood of Wistar rats at therapeutic doses and that quercetin may to produce a protective effect on this oxidative stress generated without substantially modifying the antibacterial activity of gentamicin against E. Coli strains, and it contributes to this activity against S. aureus strains.
Quercetin and Midazolam:
Mai Anh Nguyen et. al., (2015)31 investigated the effect of acute and short-term intake of high-dose quercetin on CYP3A-mediated metabolism, concluded that a single dose of quercetin was not toxic when coadministered with midazolam, whereas repeated quercetin intake can reduce systemic exposure to the orally given drug by increasing its CYP3A-catalyzed metabolism.
Quercetin and Glimeperide:
Sujatha Samala et. al., (2015)32 studied the effect of quercetin on the pharmacokinetics (PK) and pharmacodynamics (PD) of glimepiride in normal and streptozotocin induced diabetic rats. In both conditions, the co-administration of glimepiride with quercetin increased all the pharmacokinetic parameters, such as Cmax , AUC0- n, AUCtotal, t ½, MRT and decreased the clearance. Pharmacodynamic studies, suggests the enhancement of glucose reduction capacity of glimepiride in diabetic rats along with quercetin. Hence, glimepiride intake by patient require attention if co-administered with quercetin or quercetin containing herbal preparations to avoid complications. This could reduce the dose of glimepiride to achieve desired therapeutic effect with minimal adverse effects.
Quercetin and Ranolazine:
P. Ravindra Babu et. al., (2013)33 aimed to enhance the bioavailability of ranolazine by using herbal-bioenhancer quercetin in rats and to study the role of P-glycoprotein (P-gp) in vitromodels. Rats were used as experimental animal. Single and multiple dosing studies are performed. Rats were treated with drug and Bioenhancer. Blood samples were collected at specific time intervals and the concentration of ranolazine in the plasma was estimated by reverse phase high performance liquid chromatography (RP-HPLC) method. In vitro study performed on the rat and chick intestinal sacs to study the intestinal transport of ranolazine in the presence and absence of quercetin and verapamil (P-gp-inhibitor). Quercetin increased the peak concentration (Cmax) and AUC of ranolazine. The transport of ranolazine from mucosal side to serosal side was increased in presence of quercetin as it is an inhibitor of CYP3A4 and P-gp.
Quercetin and Clopidogrel:
Joo Hyun Lee et. al., (2012)34 In this study, pharmacokinetic drug interactions of clopidogrel with P-gp inhibitors in rats and dogs were studied. Following the oral administration of clopidogrel with or without the P-gp inhibitors, quercetin (250mg/kg), telmisartan (8 mg/kg), and cyclosporine A (10 mg/kg), in rats and dogs. A significantly increased the area under the curve and peak plasma concentration of clopidogrel carboxylic acid in rats. However, in dogs, the plasma concentrations of clopidogrel carboxylic acid were not considerably changed by the coadministration of three different kinds of P-gp inhibitors.
Quercetin and EGCG:
Anup Kale et. al.,(2010)35 Epigallocatechin gallate (EGCG), a anticancer component in green tea, has a poor bioavailability in rats and humans due to its metabolism and its efflux system. To calculate and compare the pharmacokinetic parameters of EGCG alone and with Quercetin/red onions this plasma concentrations of EGCG at various time intervals were determined. In rat studies, supplementation of GTE with other nutrients (E) or E + Q raised the plasma Cmax from 55.29 ± 1.70 to 61.94 ± 1.70ng/mL and 94.44 ± 1.59ng/mL, respectively. In human studies when GTE was fed as GTE or E or E + red onions, the Cmax values and AUC were increased but the change in t½ elimination was not significant. In conclusion, it is possible to increase the bioavailability of EGCG by supplementing it with nutrients and quercetin.
Quercetin and Tamoxifen:
Sang-Chul Shin a et. al., (2006)36 orally administered tamoxifen undergoes a first-pass metabolism and substrates for multidrug resistance (MDR) transporters efflux in the liver and intestines, which obstructs its systemic exposure. This study investigated the effect of quercetin, a dual inhibitor of CYP3A4 and P-gp, on the bioavailability and pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, in rats. Result shows the enhanced bioavailability of tamoxifen as a result of its coadministration with quercetin might be due to the effect of quercetin promoting the intestinal absorption and reducing the first-pass metabolism of tamoxifen.
Quercetin and Saquinavir:
Robert DiCenzo et. al., (2006)37 determined if quercetin, a bioflavonoid inhibits p-glycoprotein and alters plasma saquinavir concentrations. All human subjects received saquinavir with food for 11 days and quercetin on days 4–11. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. Plasma saquinavir concentrations were found to be similar regardless of quercetin administration. Quercetin coadministration did not influence plasma saquinavir concentrations. Because of substantial inter- and intrasubject variability, more study is necessary to determine if saquinavir intracellular concentrations are altered by coadministration of quercetin.
Quercetin and Rosiglitazone:
Kyoung-Ah Kim et. al., (2005) 38evaluated the effect of long term use of quercetin on the pharmacokinetics of rosiglitazone. After administration of quercetin or matched placebo for 3 weeks, dose of rosiglitazone was administered, and the PK data of rosiglitazone and N‐desmethylrosiglitazone were determined. Metabolic conversion based on the AUC ratio of N-desmethylrosiglitazone/rosiglitazone in the quercetin phase (0.49 ± 0.17) was similar to that of the placebo phase (0.47 ± 0.14) (P = .574). Even though the acute interaction that would occur during the first few days of concurrent administration of quercetin cannot be excluded, these results indicate that long‐term use of quercetin does not inhibit CYP2C8 activity, and the usage has little possibility of interacting with drugs that are metabolized by CYP2C8, including rosiglitazone.
Quercetin and Diltiazem:
Hoi JS, Li X et. Al (2005)39 investigated the effect of quercetin on the bioavailability of diltiazem after oral administration of diltiazem to rabbits. Both ways co-administered or pretreated with quercetin.(2, 10, 20 mg/kg) were investigated for the effect on bioavailability. The pre-treatment of Quercetin has significant effect on the plasma concentrations of diltiazem in the rabbits. The plasma concentration increased (p < 0.05, at 2mg/kg; p < 0.01, at 10 and 20 mg/kg) compared with the control, but the plasma concentrations of diltiazem co-administered with quercetin were not significant. The absolute bioavailability (AB%) of diltiazem in the rabbits pretreated with quercetin was significantly higher (9.10–12.81%) than the control (4.64%). The bioavailibility of diltiazem in the rabbits pretreated with quercetin is increased significantly compared with the control, but not in the rabbits co-administered with quercetin.
Quercetin and Verapamil:
Jun-Shik Choi et. al., (2004) 40studied the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits after oral administration in presence and absence of quercetin. Quercetin was co-administration with verapamil and results showed no effect on enhancement of the oral exposure of verapamil, whereas pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. There was no significant change in Tmax and terminal plasma half-life (t½) of verapamil in the presence of quercetin. Results implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil.
CONCLUSION:
Our ayurveda have mention a thousand of herbal drugs and extract for the various diseases and rare disease also. Ayurveda also made a major contribution in the drug discovery process in pharmacology. Today the need of Medical field is the collaborative treatment of allopathy and ayurvedic for synergistic effect. About 90% drugs are poorly bioavailable due to which treatment became costly, more side effects, and more dose interval. Hence formulations containing natural bioenhancers with enhanced bioavailability and efficacy of active ingredients will open up a new hope in the field of pharmaceutical and healthcare sector. The advantage of above formulating technique results in reduced dose and cost along with safety and efficacy. Today a lot of research is going on various classes’ of bioactives for their bioenhancing ability so that more and more, better pharmaceutical formulations come in the markets.
REFERENCES:
1. Dahan A, Miller JM, Amidon GL. “Prediction of solubility and permeability class membership. Provisional BCS classification of worlds top oral drugs”, AAPS. 2009, 11(4): 740-746.
2. Ajazuddin , Alexander A., Qureshi A., Kumari L. , Pramudita V., Sharma M. , Saraf B. “Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients”, Fitoterapia, 2014:1-14.
3. Dudhatra, G.B., Mody, S.K., Awale, M.M., Patel, H.B., Modi, C.M., Kumar, A., Kamani, D.R. and Chauhan, B.N., “A comprehensive review on pharmacotherapeutics of herbal bioenhancers”, The Scientific World Journal, pp.1-33.
4. Shailendra Wadhwa, Sarita Singhal, Swati Rawat. “Bioavailability Enhancement by Piperine: A Review”. Asian Journal of Biomedical and Pharmaceutical Sciences; 2014, 04 (36):1-8.
5. Kesarwani K, Gupta R. “Bioavailability enhancers of herbal origin: An overview”. Asian Pac J Trop Biomed 2013; 3(4):253-266.
6. Kritika Kesarwani and Rajiv Gupta, “Bioavailability enhancers of herbal origin: An overview” Asian Pac J Trop Biomed 2013; 3(4): 253-266
7. Xiao X, Shi D, Liu L, Wang J, Xie X, Kang T, “Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling”. PLoS One. 2011;6(8):e22934
8. Eid HM , Haddad PS, “The Antidiabetic Potential of Quercetin: Underlying Mechanisms.” Curr Med Chem. 2017; 24(4):355-364.
9. Vessal M, Hemmati M, Vasei M, “Antidiabetic effects of quercetin in streptozocin-induced diabetic rats” Comp Biochem Physiol C Toxicol Pharmacol. 2003 Jul;135C(3):357.
10. Dong Kwon Yang and Hyung-Sub Kang, “Anti-Diabetic Effect of Cotreatment with Quercetin and Resveratrol in Streptozotocin-Induced Diabetic Rats,” Biomol Ther (Seoul). 2018 Mar; 26(2): 130–138.
11. MohammedBule,AhmedAbdurahman,ShekoufehNikfar,MohammadAbdollahi,MohsenAmini, “Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies,” Food and Chemical toxicology,2019,125:494-502.
12. Soheir E kotob*, Alaa H sayed, Safaa H mohamed, Hanaa H ahmed, “Quercetin and ellagic acid in gastric ulcer prevention: An integrated scheme of the potential mechanisms of action from in vivo study,” Asian Journal of Pharmaceutical and Clinical research, 2018, 11(1):2455-3891.
13. Perez-Vizcaino F1, Duarte J, Jimenez R, Santos-Buelga C, Osuna A, “Antihypertensive effects of the flavonoid quercetin,” Pharmacol Rep. 2009 Jan-Feb;61(1):67-75.
14. Abigail J. Larson J. David Symons and Thunder Jalili, “Therapeutic Potential of Quercetin to Decrease Blood Pressure: Review of Efficacy and Mechanisms” American Society for Nutrition. Adv. Nutr. 2012,3: 39–46.
15. Lakhanpal P, Rai DK., “Quercetin: A versatile flavonoid,” Int J Med Update. 2007;2:22–37.
16. Graefe EU, Derendorf H, Veit M (1999). "Pharmacokinetics and bioavailability of the flavonol quercetin in humans" International Journal of Clinical Pharmacology and Therapeutics. 37 (5): 219–33.
17. Williams RJ, Spencer JP, Rice-Evans C (Apr 2004). "Flavonoids: antioxidants or signalling molecules?" Free Radical Biology & Medicine. 36 (7): 838–49.
18. Barnes S, Prasain J, D'Alessandro T, Arabshahi A, Botting N, Lila MA, Jackson G, Janle EM, Weaver CM. "The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems". Food & Function. 2011,2 (5): 235–44.
19. Horbowicz M. “Method of quercetin extraction from dry scales of onion.” Veget. Crops Res. Bull, 2002. 57: 119-124
20. Min-Jung Ko , Chan-Ick Cheigh, Sang-Woo Cho, Myong-Soo Chung, “Subcritical water extraction of flavonol quercetin from onion skin,” Journal of Food Engineering, 2011,102:327–333.
21. M.T. Munir, Hamid Kheirkhah, Saeid Baroutian, Siew Young Quek, Brent R., “Subcritical water extraction of bioactive compounds from waste onion skin,” Young Journal of Cleaner Production 183 (2018).
22. Kumar B, Smita K and Kumar B, “Ultrasound assisted extraction of quercetin from cabbage,” Int J Pharm Sci & Res 2014; 5(9): 3779-83
23. Mi Jang, Leonid Asnin, Shivraj Hariram Nile, Young Soo Keum, Hwang Yeon Kim & Se Won Park, International Journal of Food Science and Technology 2012, 1-7.
24. Shin SC, Choi JS, Li X. “Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats”. Int J Pharm 2006;313:144–9.
25. Dudhatra GB, Modi SK, Awale MM, Patel HB, Modi CM, Kumar A, “A Comprehensive review on Pharmacotherapeutics of herbal bioenhancers.” Scientific World Journal 2012; 1-33.
26. Sarika Narade , Yogesh Pore*, “Optimization of ex vivo permeability characteristics of berberine in presence of quercetin using 32 full factorial design”,Journal of Applied Pharmaceutical Science, 2019, 9(01), 073-082.
27. Manodeep Chakrabortya, *, Mohammed Gulzar Ahmedb , Ananya Bhattacharjee, “Effect of quercetin on myocardial potency of curcumin against ischemia reperfusion induced myocardial toxicity”, Synergy , 2018,7: 25–29.
28. Qingling Zhao, Jinlan Wei & Hongying Zhang, “Effects of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats”, Xenobiotica, 2018, 49(5):1-14.
29. Fei-Fei Jia, Zhi-Rong, “Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers”, Xenobiotica, 2016, 46(10):896-900.
30. Pamela Soledad Bustosa, Romina Deza-Ponzio, “Protective effect of quercetin in gentamicin-induced oxidative stressin vitro and in vivo in blood cells. Effect on gentamicin antimicrobialactivity”, Environmental Toxicology and Pharmacology, 2016, 48, 253–264.
31. Mai Anh Nguyen, Petra Staubach, “The Influence of Single-Dose and Short-Term Administration of Quercetin on the Pharmacokinetics of Midazolam in Humans“, Journal of Pharmaceutical Sciences, 2015,104,3199–3207.
32. Sujatha Samala and Ciddi Veeresham, “Altered Pharmacokinetics and Pharmacodynamics of Glimepiride by the concomitant use of Quercetin in diabetic rats: PK/PD modelling”, Journal of Pharmacy Research 2015,9(8) :525-530.
33. P. Ravindra Babu , K. Naveen Babu , P. L. Haroled Peter , K. Rajesh , and P. Jawahar Babu , “Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models”, Drug Development and Industrial Pharmacy, 2013; 39(6): 873–879.
34. Joo Hyun Lee, Yong-Jun Shin, “Pharmacokinetic Interactions of Clopidogrel with Quercetin,Telmisartan, and Cyclosporine A in Rats and Dogs”, Arch Pharm Res. 2012, 35(10):1831-7.
35. Anup Kale, Sonia Gawande,Swati Kotwal, Shrirang Netke, Waheed Roomi,Vadim Ivanov, Aleksandra Niedzwiecki and Matthias Rath, “Studies on the effects of oral administration of nutrient mixture, quercetin and red onions on the bioavailability of epigallocatechin gallate from green tea extract”, Phytother. Reserch, 2010, 24: S48–S55.
36. Sang-Chul Shin a, Jun-Shik Choi, “Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats”, International Journal of Pharmaceutics, 2006, 313:144–149.
37. Robert DiCenzo, Valerie Frerichs, “Effect of Quercetin on the Plasma and Intracellular Concentrations of Saquinavir in Healthy Adults,” Pharmacotherapy, 2006, 26(9):1256-1261.
38. Kyoung-Ah Kim, Pil-Whan Park, “Effect of Quercetin on the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate in Healthy Subjects”,Journal of Clinical Pharmacology, 2005;45:941-946.
39. J.-S. Choi, X. Li , “Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits,” International Journal of Pharmaceutics 297 (2005): 1–8.
40. Jun-Shik Choi and Hyo-Kyug Han, “The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits”, Journal of Pharmacy and Pharmacology 2004, 56: 1537–1542.
41. Javed, S., Ahsan, W. and Kohli, K., “.The concept of bioenhancers in bioavailability enhancement of drugs–a patent review” ,Journal of Scientific Letters,:143-165.
42. Prakash, S, Kherde, P. and Rangari, V., “Bioenhancement effect of piperine and ginger oleo resin on the bioavailability of atazanvir”. Int. J. Pharmacy and Pharm. Sciences, 2015, pp.241-245.
43. Balakrishnan, V., Varma, S. and Chatterji, D., 2001. Piperine augments transcription inhibitory activity of rifampicin by several fold in Mycobacterium smegmatis. Current Science, pp.1302-1305.
44. Hollman, P.C., Van Trijp, J.M., Buysman, M.N., vd Gaag, M.S., Mengelers, M.J., De Vries, J.H. and Katan, M.B., 1997. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS letters, 418(1-2), pp.152-156.
45. Ow, Y.Y. and Stupans, I., 2003. Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes. Current Drug Metabolism, pp.241-248.
Received on 20.07.2019 Modified on 10.09.2019
Accepted on 27.10.2019 © RJPT All right reserved
Research J. Pharm. and Tech 2020; 13(4):2043-2050.
DOI: 10.5958/0974-360X.2020.00368.6