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Shastrala et al. Future Journal of Pharmaceutical (2021) 7:99Future Journal ofPharmaceutical SciencesRESEARCHOpen AccessSynthesis, characterization, andpharmacological evaluation of some metalcomplexes of quercetin as P-gp inhibitorsKirankumar Shastrala1, Sirisha Kalam1* , Kumaraswamy Damerakonda1, Sharvana Bhava Bandaru Sheshagiri1,Hitesh Kumar1, Ramu Guda2, Mamatha Kasula2* and Satish Kumar Bedada3AbstractBackground: Six different metal complexes of quercetin (Cu, Zn, Co, Vd, Mo, Ni) were synthesized, purified, andcharacterized by their physical and spectral (UV, IR) data. They were evaluated for their P-gp (permeabilityglycoprotein) inhibitory activity by in vitro everted sac method in rats. The apparent permeability of atorvastatin (Pgp substrate) from everted sac of the rat intestine was determined in control, standard (verapamil), and groupstreated with quercetin-metal complexes. The drug contents were analyzed by validated RP-HPLC method using amixture of acetonitrile and water (60:40 v/v) adjusted to pH 2.8 with phosphate buffer as mobile phase.Results: In vitro studies revealed that the apparent permeability of atorvastatin (P-gp substrate) across the smallintestine is much affected by the treatment with Cu/Co/Ni complexes of quercetin. The mean SD and apparentpermeability of atorvastatin decreased after pre-treatment with these metal complexes.Conclusions: The quercetin Cu/Co/Ni complexes could inhibit P-gp and increase the atorvastatin absorption.Hence, they could be considered P-gp inhibitors.Keywords: Quercetin, Metal complexes, Atorvastatin, P-gp, Inhibitors, P-glycoproteinBackgroundCancer is a dreadful disease, killing a large number of thepopulation worldwide. More than 100 different types ofcancer are reported to affect humans [1, 2]. Chemotherapyis widely used for cancer treatment but it is hinderedmostly due to the resistance of tumor cells to anticancerdrugs [3, 4]. Several mechanisms underlying drug resistance were identified. Increased efflux of drugs by cancerous cells, due to over expression of membrane transporterproteins (efflux pumps) is one of the major mechanismsdocumented. P-glycoprotein (P-gp) is the first discoveredmultidrug transporter that pumps drugs out of tumor* Correspondence: ragisirisha@gmail.com; mamatakasula@gmail.com1Departments of Pharmaceutical Chemistry and Pharmacology, VaagdeviCollege of Pharmacy, Ramnagar, Hanamkonda, Warangal, Telangana 506001,India2Department of Chemistry, Kakatiya University, Vidyaranyapuri, Warangal,Telangana 506009, IndiaFull list of author information is available at the end of the articlecells, resulting in decreased intracellular drug concentrations and thus reducing the efficacy of drugs [5]. It ispresent in several normal tissues like intestinal lining epithelium, endothelial cells, and bone marrow.Quercetin (Q) is a major naturally occurring flavonoid,belonging to the class of flavonols. It is ubiquitouslyfound in a wide variety of plant products like coffee, tea,dyes, vegetables, and fruits [6]. The beneficial effects ofquercetin are mostly due to its free radical scavenging orantioxidant property and its ability to chelate metal ions(Fe2 and Fe3 , Cu2 , Ni2 ) [7–12]. Quercetin and someof its metal complexes displayed various biological actions such as antimicrobial, antiulcer, antiallergic, antiAlzheimer’s, and anticancer [13–18]. It was reported thatquercetin could competitively inhibit the members ofMDR family, P-gp, MRP1, and BCRP [19–23]. But, hitherto, there are no reports on the P-gp inhibitory activityof quercetin-metal complexes. In this regard, the present The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 2 of 13work was aimed to synthesize, characterize, and pharmacologically evaluate the metal (M) complexes of quercetin (M Cu, Zn, Mo, VO, Ni, Co) for their P-gp (Pglycoprotein) inhibition activity by in vitro rat evertedsac method in Wistar albino rats [24, 25], as this modeldespite a few limitations is an economic, simple, andhighly efficient tool in investigating the effect of P-gp inhibitors across the small intestine of rats and serves topredict the drug absorption in humans.vanadyl sulphate monohydrate, nickel chloride hexahydrate, cobaltous chloride hexahydrate, and hydrochloricacid were purchased from Qualigens Fine Chemicals,Mumbai. Dimethyl sulfoxide, sodium hydroxide, andhexane were obtained from Finar Chemicals, Mumbai.Dulbecco’s phosphate buffer pH of 7.4 was purchasedfrom Hi Media Ltd., Mumbai, and HPLC-grade waterwas procured from S.R. Enterprises, Hanamkonda.MethodsInstrumentsDrugs and chemicalsUV-visible double-beam spectrophotometer (ShimadzuUV-1800, 240V, 2010), FT-IR spectrophotometer (Bruker ALPHA, 2011), HPLC (Cyberlab, SPD-10A UV-Visdetector, LC 10AD pump, 2011), refrigerator (LG 360L,2008), electronic weight balance (Shimadzu AUY 220,2011), sonicator (Electric supply 1.5L50, 2010), electromagnetic stirrer (Remi G3M5-3600, 2008), and vacuumdesiccators were used.The drug atorvastatin was purchased from Stallion Laboratories Pvt. Ltd., Ahmedabad; verapamil was purchased from Ranbaxy Laboratories Ltd., Hyderabad; andquercetin was obtained from Sigma Aldrich Chemicals,Bangalore. HPLC-grade methanol and acetonitrile andBDH-grade of the chemicals copper chloride dihydrate,zinc chloride hexahydrate, ammonium molybdate,Scheme 1 Synthesis of quercetin-metal (Q-M) complexes

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Table 1 Physical data of quercetin-metal complexesS. no.Metal complexesColor% Yield1Quercetin-copperBrownish yellow83.072Quercetin-zincDark brown82.633Quercetin-molybdenumDark red80.804Quercetin-vanadylBrownish yellow82.905Quercetin-nickelPale yellow80.396Quercetin-cobaltDark brown84.64AnimalsTwenty-four healthy Wistar albino adult male rats 7–9weeks of age, weighing between 200 and 250 g, procuredfrom Mahaveer Enterprises (reg no. 146/1999 CPCSEA)Hyderabad, Telangana, were used in this research work.The animals were accommodated at the animal house ofthe institute approved by the Committee for the Purpose ofControl and Supervision of Experiments on Animals(CPCSEA) (reg. no. 1047/ac/07 CPCSEA). They were maintained under standard laboratory conditions at an ambienttemperature of 25 2 C and 50 15% relative humidity,with a 12-h light/dark cycle. Rats were fed with a commercial pellet (Hindustan lever Pvt. Ltd. Mumbai, India) dietand water ad libitum. They were overnight fasted prior tothe experiment. The animal experiments were performedin accordance with the CPCSEA guidelines after prior approval of the study protocol by the Institutional AnimalEthics Committee (IAEC).Spectral analyses of quercetin complexesUV-visible study of quercetin and its metal complexes(Cu, Zn, Mo, VO, Ni, Co) were carried out in the wavelength range of 200 to 500 nm by using UV-visible spectrophotometer. Infrared spectral study of thesecomplexes was performed using IR spectrophotometerand the obtained spectral data were analyzed [9, 26, 27].Preparation of quercetin-metal complexesThe quercetin-metal complexes have been synthesizedand prepared according to previously reported method[28].The Cu(II), Zn(II), Ni(II), and Co(II) complexeswere prepared using respective metal chlorides; VO(IV)complex was prepared using vanadyl sulphate; andMo(IV) complex was prepared using its ammonium salt.In the preparation of all the metal complexes, themetal and the quercetin compounds were combined in1:2 mole ratio (the metal being in slight excess of thePage 3 of 13desired ratio) using appropriate quantities of aqueousmethanolic quercetin and methanolic or aqueous metalsalt solutions, respectively. The pH of the solutions wasadjusted to 10 by adding sodium hydroxide solution.General procedure for the preparation of quercetin-metalcomplexesTo a hot methanolic solution of quercetin taken in a 50-mltwo-necked round-bottomed flask equipped with magneticstirrer, a solution of an appropriate metal salt (copperchloride dihydrate (CuCl2·2H2O), zinc chloride hexahydrate(ZnCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O),cobaltous chloride hexahydrate (CoCl2·6H2O), vanadylsulphate monohydrate (VOSO4·H2O), ammonium molybdate ((NH4)2MoO4)) in methanol was added dropwise withstirring and the resultant mixture was heated under refluxfor 4–8 h. Obtained solids were filtered off and washed withdiethyl ether and dried under vacuum (Scheme 1).Pharmacological evaluationEverted rat sac methodThe in vitro everted sac technique was introduced by Wilson and Wiseman [29] and later modified into moderneverted sac technique. It is a simple, renowned tool tostudy various pharmacokinetic phenomena like absorption, metabolism, and interaction of drugs and to carryout studies related to multidrug resistance (MDR), role ofefflux transporters, and the effect of MDR modulators ondrug absorption in the gut. This model involves the gentleeversion of a freshly excised portion of rat small intestineusing a glass rod, clamping, and tying one end of the segment and filling it with appropriate solution, sealing theother end tightly, immersing the obtained sac in physiological solution maintained at 37 C, collecting the samples at different time intervals, and analyzing the resultsobtained. The everted sac technique measures the serosalto-mucosal transport of drug substrates [30, 31] unlike thenon-everted sac technique which measures the mucosal toserosal transport of drug substrates [32].The animals were overnight fasted and anaesthetizedusing isoflurane (2–3% by drop jar method). After anaesthetizing the animals, they were euthanized with cervicaldecapitation and the whole small intestine of each animal was isolated and flushed with 50 ml of ice-cold saline. The small intestine was divided into duodenum,jejunum, and ileum (n 3). Segments were everted, and10-cm-long sacs were prepared. About 1 ml of atorvastatinTable 2 UV-spectral data of quercetin-metal complexesBands Quercetin (Q)(nm)Cu(II)-Q complex(nm)Zn(II)-Q complex(nm)Mo(II)-Q complex(nm)VO(IV)-Q complex(nm)Ni(II)-Q complex(nm)Co(II)-Q 257263

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Table 3 HPLC profile of atorvastatinConcentration (μg/ml)Peak height lution (1 μg/ml) in DMSO was introduced into theeverted sacs (serosal side) and both ends of the sacs were ligated tightly. The sacs (n 3) containing atorvastatin solution were immersed on their mucosal side into 30 ml ofDulbecco’s phosphate buffer solution (D-PBS) containing30 μM concentration of glucose and 30 μM concentrationof quercetin-metal complexes (Q-M; M Cu, Co, Ni, Zn,Mo, VO) in DMSO. The buffer solution was prewarmedand oxygenated throughout the experiment. Similarly, thesacs (n 3) filled with atorvastatin without any inhibitor onmucosal side served as control and the sacs (n 3) filledwith the atorvastatin and verapamil (300 μM) on mucosalside served as standard [33, 34].The Everted sac model, i.e., intestinal serosal-to-mucosaltransport of atorvastatin was measured by the periodic collection of samples from the mucosal medium at differenttime intervals (0, 10, 30, 45, 60 min). All the samples weremixed with acetonitrile in 2:1 ratio, vortexed (2 min), andcentrifuged at 3000 rpm (15 min). Aliquots of supernatantwere separated, filtered through membrane filter (0.22-μmpore size) and preserved at – 20 C until analysis. Twentymicroliters of it was injected into the HPLC column using aHamilton syringe. The transport of atorvastatin in the absence of P-gp inhibitor (control), in the presence of Q-Mcomplexes (test) or verapamil (standard) was measured byFig. 1 Calibration curve of atorvastatinPage 4 of 13validated reverse-phase high-performance liquid chromatography (RP-HPLC) method [35]. Apparent permeabilitycoefficients (Papp) of atorvastatin were calculated from theequation [36] given:Papp ¼dQ 1:dt AC 0where dQ/dt is the steady-state appearance rate on theacceptor solutionA is the surface area of the intestinal sacs (7.85 cm2/sac)C0 is the initial concentration of drug (inside the sac)Sensitive RP-HPLC methodChromatographic conditionsAcetonitrile and water in the proportion of 60:40 (v/v)adjusted to pH 2.8 with phosphate buffer was used asmobile phase, stationary phase was a C-18 reverse-phasecolumn of 250 4.6 mm dimension, and 5 μ particlesize, flow rate was 1 ml/min at λ max of 247 nm, runtime was 15 min, injection volume was 20 μl, andAUFS (absorbance units full scale) was 0.005.Preparation of calibration curve of atorvastatinPreparation of stock solutionsA stock solution representing 1 mg/ml of atorvastatin wasprepared in methanol. The working standard solutionswere prepared prior to use from stock solution by sequential dilution with methanol to yield final concentrations of0.05, 0.1, 0.25, 0.5, 1, 2.5, and 5μg/ml of atorvastatin.Construction of calibration curveThe calibration curve was constructed using peak heightratios of the drug versus concentration [37]. The slopeof the plot determined by the method of linear regression analysis was used to calculate the atorvastatin

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 5 of 13Fig. 2 Chromatograms of atorvastatin in the absence of verapamilconcentration in the unknown sample. A linear regression curve in the range of 0.05 to 5 μg/ml wasestablished.Statistical analysisThe in vitro results were compared by Student’spaired t-test using Graph Pad Instant Softwareversion-5.0. A value of p 0.05 was considered statistically significant.ResultsChemistryAddition of aqueous sodium hydroxide during the synthesis of metal complexes resulted in the deprotonationof the OH groups and thus favored the stability of quercetin at pH 10. All the metallic salts were soluble in thereaction mixture except cobaltous chloride hexahydratewhich was dissolved using dimethyl formamide. All thequercetin-metal complexes were obtained in good yieldsranging from 80.39 to 84.64% as indicated in Table 1.

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 6 of 13Fig. 3 Chromatograms of atorvastatin in presence of verapamil (300 μM)UV-visible study of the quercetin-metal complexesThe UV-visible spectrum of quercetin in DMSO andphosphate buffer shows two major absorption bands dueto π-π* transitions at 369 (band-I) and 252 nm (band-II)(Table 2). When the solution of a metallic salt was added,bands I and II gradually shifted to longer wavelengths,accompanied with slight decrease in absorption. The resultsindicated formation of a complex between quercetin andrespective metal ions. Band-I bathochromic shift (401 nm)is a common feature observed with all the quercetin-metalcomplexes. It could be due to the interaction of metal ions(Cu, Zn, Co, VO, Mo, and Ni) with the 3-hydroxy and 4-

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 7 of 13Fig. 4 Chromatograms of atorvastatin in presence of quercetin-copper complex (30 μM)carbonyl groups, the two possible chelating sites on quercetin resulting in electronic redistribution between thequercetin molecule and metal ion.Infrared spectral study of the quercetin-metal complexesQuercetin showed peaks at 3417 cm 1(broad) for O-Hstretch, 1665 cm 1for C O stretch, 1510 cm 1for C Cstretch, 1316 cm 1for OH bend, 1243 cm 1 for C-Ostretch, and 1162 cm 1 and 997 cm 1 for CH bend.The presence of peaks at 3355, 3370, 3398, 3325,3379, and 3395 cm 1 in IR spectra of the quercetinmetal complexes indicate the formation of O-Cu, OZn, O-Mo, O-VO, O-Ni, and O-Co bonds,respectively, through the complexes [27, 38]. The C O stretching mode of the free ligand (quercetin) occurs at 1665 cm 1. By the interaction of ligand withcopper acetate/zinc chloride/ammonium molybdate/vanadyl sulphate monohydrate/ammonium nickelsulphate hexahydrate/cobaltous chloride hexahydrate,it has been shifted to 1655, 1658, 1633, 1637, 1627,and 1637 cm 1, respectively, which can be explainedby coordination of carbonyl oxygen with Cu2 , Zn2 ,Mo2 , vo2 , Ni2 , and Co2 ions, respectively. Moreover, an increase in bond order from 1316 cm 1inligand to 1346, 1342, 1325, 1342, 1352, and 1371cm 1, respectively, after complexation with copper,

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 8 of 13Fig. 5 Chromatograms of atorvastatin in presence of quercetin-cobalt complex (30 μM)zinc, molybdenum, vanadium, nickel, and cobalt ions, respectively, indicates the involvement of O-H deformationvibration which co-ordinates in metal chelation.Everted rat sac methodIn the present study, the amount of atorvastatintransported from everted sacs (serosal-to-mucosalsurface) was determined in different regions of the ratintestine. Control was compared with the standard Pgp inhibitor (verapamil) and quercetin-metal (Q-M)complexes (M Cu, Zn, Mo, VO, Ni, Co). The transport of atorvastatin across the everted intestinal sacswas determined and expressed as mean SD (standard deviation).

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 9 of 13Fig. 6 Chromatograms of atorvastatin in presence of quercetin-nickel complex (30 μM)Table 4 Apparent permeability coefficients (Papp) ( 10 6 cm/s) of atorvastatin in the everted duodenum of healthy rat smallintestine (n 3)Time Duodenum(min)Atorvastatintreated ratsAtorvastatin verapamil-treated ratsAtorvastatin Q-Cucomplex-treated ratsAtorvastatin Q-Cocomplex-treated ratsAtorvastatin Q-Nicomplex-treated rats100.030 0.0030.028 0.0010.035 0.0010.035 0.0010.042 0.001300.036 0.0030.026 0.0020.024 0.0010.019 0.0010.027 0.000450.073 0.0190.022 0.002*0.023 0.001*0.012 0.001**0.020 0.001*600.119 0.0600.010 0.002***0.021 0.001***0.010 0.0004***0.009 0.0001***All values expressed as mean SD. *p 0.05 significant, **p 0.01 highly significant, ***p 0.001 very highly significant, compared to atorvastatin control

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99Page 10 of 13Table 5 Apparent permeability coefficients (Papp) ( 10 6 cm/s) of atorvastatin in the everted jejunum of healthy rat small intestine(n 3)Time Jejunum(min)Atorvastatintreated ratsAtorvastatin verapamil-treated ratsAtorvastatin Q-Cucomplex-treated ratsAtorvastatin Q-Cocomplex-treated ratsAtorvastatin Q-Nicomplex-treated rats100.034 0.0040.032 0.0020.027 0.0010.028 0.0010.031 0.001300.042 0.0040.028 0.0020.022 0.0020.017 0.0020.022 0.001450.078 0.0190.026 0.0030.020 0.002*0.012 0.001*0.016 0.001*600.131 0.0740.023 0.004**0.019 0.002**0.009 0.0005**0.007 0.0002**All values expressed as mean SD. *p 0.05 significant, **p 0.001 very highly significant, compared to atorvastatin controlRP-HPLC method of analysisIn the present study, the atorvastatin concentrationswere estimated by a sensitive RP-HPLC method (Table3). The calibration curve of atorvastatin was plotted withconcentration versus peak height as shown in Fig. 1. Thetypical chromatograms corresponding to solvent bufferand atorvastatin in the absence and presence of verapamil and in the presence of quercetin-metal complexesat different time points of the experimental study aredepicted in Figs. 2, 3, 4, 5, and 6. The separation of bothpeaks (solvent and atorvastatin) was satisfactory, with retention times of 2.46 min and 3.30 min, respectively.Tables 4, 5, and 6 reveal the apparent permeability coefficients (Papp) of atorvastatin alone (control) and inpresence of verapamil (standard) and the quercetinmetal complexes (test) in the everted duodenum, jejunum, and ileum, respectively.DiscussionClinically, multidrug resistance (MDR) is one of the majorcauses for chemotherapeutic treatment failure in cancerpatients. Several strategies for overcoming drug resistancehave been studied, including (1) developing reversal agentswhich target drug resistance markers such as P-gp andMRP1, (2) developing new agents to which drug-resistantcancer cells are sensitive, (3) employing agents to whichdrug-resistant cancer cells show collateral sensitivity, and(4) developing antiangiogenesis therapy and gene therapyfor drug-resistant cancer cells [39]. Among them,developing reversal agents which target P-gp has been aprincipal strategy.Multidrug resistance of cancer cells is often associatedwith over expression of P-gp, a plasma membrane transporter that extrudes chemotherapeutic drugs by usingATP hydrolysis as the energy source. P-gp is encoded bythe MDR1 gene and functions as an energy-dependentmultidrug membrane transporter that rapidly extrudes avariety of hydrophobic anticancer drugs from target cancer cells and thereby prevents the drugs from exertingcytotoxic effects. Since the first P-gp inhibitor, verapamil, was found in 1981, a variety of agents includingcyclosporin A (CysA) and others have been reported asagents for overcoming MDR [40].However, the clinical trial results of these drugs arevery disappointing so far, due to dose-limiting toxicity. Therefore, it is necessary to find new reversingagents with lesser side effects. Natural sources comeunder this category of having no dose-limiting toxicityand lesser side effects [41, 42]. Several members offlavonoids were found to be able to modulate drug efflux in MDR cancer cells, such as genistein, quercetin,and naringenin [43, 44]. The flavonoid quercetin wasshown to inhibit P-gp-mediated drug transport byinhibiting the ATP binding site of P-gp. It was reported to decrease the expression of P-gp significantlyin multidrug-resistant human cervical carcinoma (KBV1) cells at the concentration of 30 μM [45].Experimental studies proved that quercetin exhibitsboth P-gp inhibitory and antitumor activities and it alsoTable 6 Apparent permeability coefficients (Papp) ( 10 6 cm/s) of atorvastatin in the everted ileum of healthy rat small intestine (n 3)Time Ileum(min)Atorvastatintreated ratsAtorvastatin verapamil-treated ratsAtorvastatin Q-Cucomplex-treated ratsAtorvastatin Q-Cocomplex-treated ratsAtorvastatin Q-Nicomplex-treated rats100.040 0.0030.041 0.0020.023 0.0010.022 0.0020.023 0.0006300.046 0.0040.036 0.0030.019 0.0010.015 0.0010.018 0.001450.085 0.0210.033 0.0020.018 0.0010.009 0.0010.013 0.001600.169 0.1220.032 0.003*0.016 0.001**0.007 0.0001**0.005 0.0002**All values expressed as mean SD. *p 0.01 highly significant, **p 0.001 very highly significant, compared to atorvastatin control

Shastrala et al. Future Journal of Pharmaceutical Sciences(2021) 7:99has the ability to chelate metal ions [16]. Further, somemetal complexes show P-gp inhibitory activity [46–48].But till now, there are no reports on P-gp inhibitory activity of quercetin-metal complexes.In the present study, we have synthesized metal(Cu, Co, Ni, Zn, Mo, VO) complexes of quercetin inhigh yields and purity and characterized them byusing UV-visible and IR spectral data. From spectroscopic studies, quercetin was found to chelate metalions (Cu, Co, Ni, Zn, Mo, VO) at the 3-hydroxy and4-carbonyl groups. They were pharmacologically evaluated for their P-gp inhibitory activity by in vitroeverted sac method in rats by comparing the apparentpermeability of P-gp substrate (atorvastatin) with thatof standard P-gp inhibitor, verapamil.Results of this in vitro study revealed that thetransport of atorvastatin (P-gp substrate) across thesmall intestine is much affected by the Q-Cu, Q-Co,and Q-Ni complex treatment. The mean SD andapparent permeability of atorvastatin decreased inthe presence of the Q-Cu, Q-Co, and Q-Ni complexes. A time-dependent effect was observed. Also,a significant reduction in the Papp values was observed in the everted sacs treated with Q-Cu, Q-Co,and Q-Ni complexes as compared with controls. Allthe three metal complexes were found to be morepotent than the standard verapamil at all three sitesof small intestine (i.e., duodenum, jejunum, andileum) at only one-tenth dose of verapamil. Amongthe three complexes, Q-Ni complex exhibited superior inhibitory activity on the permeability glycoprotein (P-gp). Next to it, Q-Co complex significantlyreduced the transport of atorvastatin across the intestinal membranes. The rest of the complexes (QMo, Q-Zn, Q-VO) did not show any effect on thetransport of atorvastatin and hence considered inactive. The study revealed that Q-Cu, Q-Co, and QNi metal complexes could inhibit P-gp (at muchlesser concentrations than verapamil) and increasethe absorption of atorvastatin.ConclusionThe transport of atorvastatin (P-gp substrate) across thesmall intestine is much affected by the Q-Cu, Q-Co, andQ-Ni complexes treatment. The treatment of sacs withthese metal complexes decreased the intestinal permeation of atorvastatin (P-gp substrate) when comparedwith that of standard P-gp inhibitor and control, whichmay be due to inhibition of P-glycoprotein. Hence, theycould be considered P-gp inhibitors and studied further.AbbreviationsRP-HPLC: Reverse-phase high-performance liquid chromatography;MDR: Multidrug resistance; M: Metal; Q: Quercetin; Q-Cu: Quercetin-coppercomplex; Q-Zn: Quercetin-zinc complex; Q-Mo: Quercetin-molybdenumPage 11 of 13complex; Q-Vo: Quercetin-vanadyl complex; Q-Ni: Quercetin-nickel complex;Q-Co: Quercetin-cobalt complex; P-gp: P-glycoprotein (permeabilityglycoprotein); SD: Standard deviation; UV: Ultraviolet spectrophotometer;IR: Infrared spectrophotometer; CPCSEA: Committee for the Purpose ofControl and Supervision of Experiments on Animals; IAEC: InstitutionalAnimal Ethics CommitteeAcknowledgementsThe authors are thankful to the Management, Principal, and H.O.D(Pharmacology) for providing the necessary facilities.Authors’ contributionsSK conceptualized the project and gave technical inputs in conducting thestudy and preparing manuscript. KS performed the entire study under theguidance of SK. HK assisted KS during the experimental work. KD preparedthe manuscript. SBBS and SKB gave technical inputs in conducting theanimal studies, analyzing the results, drafting the manuscript, andsubstantively revised it. RG assisted KS in synthesizing the metal complexes,under the guidance of MK. The authors have read and approved themanuscript.FundingNone.Availability of data and materialsAll data and materials are available upon request.DeclarationsEthics approval and consent to participateThe animal experiments were performed after prior approval of the studyprotocol by the Institutional Animal Ethics Committee (application no. 44/IAEC/VCOP/2013).Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1Departments of Pharmaceutical Chemistry and Pharmacology, VaagdeviCollege of Pharmacy, Ramnagar, Hanamkonda, Warangal, Telangana 506001,India. 2Department of Chemistry, Kakatiya University, Vidyaranyapuri,Warangal, Telangana 506009, India. 3Clinical Development Division, SanofiIndia, South Goa, Goa 403722, India.Received: 13 January 2021 Accepted: 26 April 2021References1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics. CA A Cancer J Clin70(1):7–30. https://doi.org/10.3322/caac.215902. Smith RD, Mallath MK (2019) History of the growing burden of cancer inIndia: from antiquity to the 21st century. J Glob Oncol 5:1–15. https://doi.org/10.1200/JGO.19.000483. Zheng HC (2017) The molecular mechanisms of chemoresistance in cancers.Oncotarget 8(35):59950–59964. https://doi.org/10.18632/oncotarget.190484. Schirrmacher V (2019) From chemotherapy to biological therapy: a reviewof novel concepts to reduce the side effects of systemic cancer treatment(Review). Int J Oncol 54(2):407–419. https://doi.org/10.3892/ijo.2018.46615. Wang X, Zhang H, Chen X (2019) Drug resistance and combating drugresistance in cancer. Cancer Drug Resist 2:141–1606. Salehi B, Machin L, Monzote L, Sharifi-Rad J, Ezzat SM, Salem MA, MerghanyRM, El Mahdy NM, Kılıç CS, Sytar O, Sharifi-Rad M, Sharopov F, Martins N,Martorell M, Cho WC (2020) Therapeutic potential of quercetin: new insightsand perspectives for human health. ACS Omega 5(20):11849–11872. https://doi.org/10.1021/acsomega.0c018187. Lesjak M, Beara I, Simin N, Pintać D, Majkić T, Bekvalac K, Orčić D, Mimica-DukićN (2018) Antioxidant and anti-inflammatory activities of quercetin and itsderivatives. J Funct Foods 40:68–75. https://doi.org/10.1016/j.jff.2017.10.047

Shastrala et al. Future Journal of Pharmaceutical .23.24.25.26.27.(2021) 7:99Xu D, Hu M-J, Wang Y-Q, Cui Y-L (2019) Antioxidant activities of quercetinand its complexes for medicinal application. Molecules s24061123Torreggiani A, Tamba M, Trinchero A, Bonora S (2005) Copper (II)–quercetincomplexes in aqueous solutions: spectroscopic and kinetic properties. J MolStruct 744–747:759–766De Castilho TS, Matias TB, Nicolini KP, Nicolini J (2018) Study of interactionbetween metal ions and quercetin. Food Sci Human We

chloride dihydrate (CuCl 2·2H 2O), zinc chloride hexahydrate (ZnCl 2·6H 2O), nickel chloride hexahydrate (NiCl 2·6H 2O), cobaltous chloride hexahydrate (CoCl 2·6H 2O), vanadyl sulphate monohydrate (VOSO 4·H 2O), ammonium molyb-date ((NH 4) 2MoO 4)) in methanol was added dropwise with stirring and the resultant mixture was heated under .

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Phytochemical analysis for major classes of metabolites is an important first step in pharmacological evaluation of plant extracts. Some journals require that pharmacological studies be accompanied by a comprehensive phytochemical analysis. Details of such analysis are found in several text books (Harborne, 1984; Evans, 2009). The main secondary metabolite classes include flavonoids .

of treatment with a similar success rate and safety profile. Undoubtedly, a large randomised control trial, ideally in-cluding a group without pharmacological thromboprophy-laxis, is needed to draw more definitive conclusions on the optimal duration of pharmacological post-EVLA thro

and this is still in the form of a PID controller but now the settings are: 2Ip W p c W T p c p K K, W W, and W T 1 Dp. . Colorado School of Mines CHEN403 Direct Synthesis Controller Tuning Direct Synthesis - Direct Synthesis - Direct Synthesis - Colorado School of Mines CHEN403 Direct Synthesis Controller Tuning File Size: 822KB