Influence of Quercetin Pretreatment on Pharmacokinetics of Warfarin in
Rats

Ejaz      Ahmad; Muhammad      Jahangir; Muhammad   Akhter   Ismail; Hafsa      Afzal; Shehar      Bano; Rahat      Shamim; Nadeem   Irfan   Bukhari

Abstract

Background: Warfarin (WAR) is an anticoagulant with a narrow therapeutic index and is principally metabolized by CYP3A4 and CYP2C9 enzymes. The inhibitors of these enzymes may alter the systemic exposure to WAR. Quercetin (QUE), a bioflavonoid, may modify the bioavailability of drugs used concurrently by inhibiting CYP3A4, CYP2C8, CYP2C9, CYP1A2, and Pglycoprotein (P-gp).

Objective: The current study scrutinized the influence of QUE on WAR pharmacokinetics in rats.

Method: QUE was orally administered to animals for 14 consecutive days, followed by WAR as a single oral dose on the 15^th day in the pre-treatment group. The co-administration group received a single dose of QUE and WAR concomitantly. Only carboxymethylcellulose (CMC) 0.5% was administered as a vehicle to control group.

Results: In the pre-treated group, WAR’s C_max was increased by 30.43%, AUC_0-∞ by 62.94%, and t_1/2 by 10.54%, while Cl decreased by 41.35%, relative to control. In co-administered animals, WAR’s C_max increased by 10.98%, AUC_0-∞ by 20.20%, and t_1/2 by 8.87%, while Cl declined by 16.40%.

Conclusion: QUE alters the pharmacokinetics of WAR, warranting possibly WAR dose adjustment after confirmatory clinical investigations, specifically in patients with thrombotic disorders and a pre-treatment history of QUE or its product.

Keywords: Quercetin, warfarin, bioavailability, pharmacokinetic, drug, interactions.

« Previous Next »

Graphical Abstract

[1]
Alalwan AA, Voils SA, Hartzema AG. Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation. Am J Health Syst Pharm  2017; 74(16): 1237-44.
 [http://dx.doi.org/10.2146/ajhp160756] [PMID: 28652320]

[2]
Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. Executive summary: Antithrombotic therapy and prevention of thrombosis.  (9th ed.). American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: pp. (2)7S-47S.
 [http://dx.doi.org/10.1378/chest.1412S3] [PMID: 22315257]

[3]
Jacobs LG. Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly. Cardiol Clin  2008; 26(2): 157-67.
 [http://dx.doi.org/10.1016/j.ccl.2007.12.010] [PMID: 18406992]

[4]
Krynetskiy E, McDonnell P. Building individualized medicine: Prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther  2007; 322(2): 427-34.
 [http://dx.doi.org/10.1124/jpet.106.117952] [PMID: 17496169]

[5]
Ouirke W, Cahill M, Perera K, Sargent J, Conway J. Warfarin prevalence, indications for use and haemorrhagic events. Ir Med J  2007; 100(3): 402-4.
 [PMID: 17491542]

[6]
Tadros R, Shakib S. Warfarin: Indications, risks and drug interactions. Aust Fam Physician  2010; 39(7): 476-9.
 [PMID: 20628660]

[7]
Turakhia MP. Quality of stroke prevention care in atrial fibrillation: Many moving targets. Circ Cardiovasc Qual Outcomes  2011; 4(1): 5-8.
 [http://dx.doi.org/10.1161/CIRCOUTCOMES.110.959890]

[8]
Hussain MS. Patient counseling about herbal-drug interactions. Afr J Tradit Complement Altern Med  2011; 8(5): 152-63.
 [PMID: 22754069]

[9]
Anthony CJ, Karim S, Ackroyd-Stolarz S, et al. Intensity of anticoagulation with warfarin and risk of adverse events in patients presenting to the emergency department. Ann Pharmacother  2011; 45(7-8): 881-7.
 [http://dx.doi.org/10.1345/aph.1P670] [PMID: 21750309]

[10]
Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med  2007; 147(11): 755-65.
 [http://dx.doi.org/10.7326/0003-4819-147-11-200712040-00006] [PMID: 18056659]

[11]
Hansen PW, Sehested TSG, Fosbøl EL, et al. Trends in warfarin use and its associations with thromboembolic and bleeding rates in a population with atrial fibrillation between 1996 and 2011. PLoS One  2018; 13(3): e0194295.
 [http://dx.doi.org/10.1371/journal.pone.0194295] [PMID: 29547673]

[12]
Hogan RPJJ. Hemorrhagic diathesis caused by drinking an herbal tea. JAMA  1983; 249(19): 2679-80.

[13]
Horton JD, Bushwick BM. Warfarin therapy: Evolving strategies in anticoagulation. Am Fam Physician  1999; 59(3): 635-46.
 [PMID: 10029789]

[14]
Soyata A, Nur Hasanah A, Rusdiana T. Interaction of warfarin with herbs based on pharmacokinetic and pharmacodynamic parameters. Indones J Pharm  2020; 2(2): 69-76.
 [http://dx.doi.org/10.24198/idjp.v2i2.27289]

[15]
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med  2011; 365(2): 147-56.
 [http://dx.doi.org/10.1056/NEJMra1011170] [PMID: 21751907]

[16]
Badri S, Mohammadi S, Asghari G, Emami-Naini A, Mansourian M. Herbal supplement use and herb–drug interactions among patients with kidney disease. J Res Pharm Pract  2020; 9(2): 61-7.
 [http://dx.doi.org/10.4103/jrpp.JRPP_20_30] [PMID: 33102379]

[17]
Patel JA, Gohil KJ. Herb-drug interactions: A review and study based on assessment of clinical case reports in literature. Indian J Pharmacol  2007; 39(3): 129.
 [http://dx.doi.org/10.4103/0253-7613.33432]

[18]
de Lima Toccafondo Vieira M, Huang SM. Botanical-drug interactions: A scientific perspective. Planta Med  2012; 78(13): 1400-15.
 [http://dx.doi.org/10.1055/s-0032-1315145] [PMID: 22864989]

[19]
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest  2012; 141(2) (Suppl.): e44S-88S.
 [http://dx.doi.org/10.1378/chest.11-2292] [PMID: 22315269]

[20]
Siddiqi A, Khan DA, Khan FA, Naveed AK. Impact of CYP2C9 genetic polymorphism on warfarin dose requirements in Pakistani population. Pak J Pharm Sci  2010; 23(4): 417-22.
 [PMID: 20884456]

[21]
Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol  2005; 45(2): 127-32.
 [http://dx.doi.org/10.1177/0091270004271404] [PMID: 15647404]

[22]
Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J  2005; 5(4): 262-70.
 [http://dx.doi.org/10.1038/sj.tpj.6500313] [PMID: 15883587]

[23]
Strohecker J, Carbajal D, Crandall B, Day J, Lappe D, Mahapatra S. Herbal and non-herbal supplement use is common in warfarin-treated patients and the majority of these agents impact warfarin safety and efficacy. J Innov Card Rhythm Manag  2012; 3: 611-9.

[24]
Krishna S, Aiswarya P. Warfarin interactions with complementary medicines, herbs and dietary supplements. J Chem Pharm Res  2015; 7(6): 71-5.

[25]
Page RL II, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy  1999; 19(7): 870-6.
 [http://dx.doi.org/10.1592/phco.19.10.870.31558] [PMID: 10417036]

[26]
Sunter W. Warfarin and garlic. Pharm J  1991; 246.

[27]
Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St. John’s wort drug interactions. Eur J Clin Pharmacol  2006; 62(3): 225-33.
 [http://dx.doi.org/10.1007/s00228-006-0096-0] [PMID: 16477470]

[28]
Turfan M, Tasal A, Ergun F, Ergelen M. A sudden rise in INR due to combination of Tribulus terrestris, Avena sativa, and Panax gin- seng (Clavis Panax). Turk Kardiyol Dern Ars  2012; 40(3): 259-61.
 [http://dx.doi.org/10.5543/tkda.2012.45793] [PMID: 22864323]

[29]
Dean L. Warfarin therapy and the genotypes CYP2C9 and VKORC1. Medical Genetics Summaries  2012; 2: 257-63.

[30]
Hertog MGL, Hollman PCH, Venema DP. Optimization of a quantitative HPLC determination of potentially anticarcinogenic flavonoids in vegetables and fruits. J Agric Food Chem  1992; 40(9): 1591-8.
 [http://dx.doi.org/10.1021/jf00021a023]

[31]
Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev  2016; 68(1): 168-241.
 [http://dx.doi.org/10.1124/pr.115.011411] [PMID: 26721703]

[32]
Hu Z, Yang X, Ho PCL, et al. Herb-drug interactions. Drugs  2005; 65(9): 1239-82.
 [http://dx.doi.org/10.2165/00003495-200565090-00005] [PMID: 15916450]

[33]
Choi JH, Kim KJ, Kim SJJB. Comparative effect of quercetin and quercetin-3-O-β-d-glucoside on fibrin polymers, blood clots, and in rodent models. J Biochem Mol Toxicol  2016; 30(11): 548-58.
 [http://dx.doi.org/10.1002/jbt.21822]

[34]
Ferenczyova K, Kalocayova B, Bartekova M. Potential implications of quercetin and its derivatives in cardioprotection. Int J Mol Sci  2020; 21(5): 1585.
 [http://dx.doi.org/10.3390/ijms21051585] [PMID: 32111033]

[35]
Zhang YM, Zhang ZY, Wang RX. Protective mechanisms of quercetin against myocardial ischemia reperfusion injury. Front Physiol  2020; 11: 956.
 [http://dx.doi.org/10.3389/fphys.2020.00956] [PMID: 32848878]

[36]
Alnaqeeb M, Mansor KA, Mallah EM, Ghanim BY, Idkaidek N, Qinna NA. Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts. BMC Complement Altern Med  2019; 19(1): 29.
 [http://dx.doi.org/10.1186/s12906-019-2436-5] [PMID: 30678660]

[37]
Zhou S, Chan E, Li X, Huang M. Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4. Ther Clin Risk Manag  2005; 1(1): 3-13.
 [http://dx.doi.org/10.2147/tcrm.1.1.3.53600] [PMID: 18360537]

[38]
Rodrigues M, Alves G, Francisco J, Fortuna A, Falcão A. Herb-drug pharmacokinetic interaction between Carica papaya extract and amiodarone in rats. J Pharm Pharm Sci  2014; 17(3): 302-15.
 [http://dx.doi.org/10.18433/J3559N] [PMID: 25224345]

[39]
Rodrigues M, Alves G, Lourenço N, Falcão A. Herb-Drug interaction of Paullinia cupana (Guarana) seed extract on the pharmacokinetics of Amiodarone in rats. J Evidence-Based Complementary Altern Med  2012; 2012: 1-11.

[40]
Rodrigues M, Alves G, Abrantes J, Falcão A. Herb–drug interaction of Fucus vesiculosus extract and amiodarone in rats: A potential risk for reduced bioavailability of amiodarone in clinical practice. Food Chem Toxicol  2013; 52: 121-8.
 [http://dx.doi.org/10.1016/j.fct.2012.11.012] [PMID: 23178632]

[41]
Otali D, Fredenburgh J, Oelschlager DK, Grizzle WE. A standard tissue as a control for histochemical and immunohistochemical staining. Biotech Histochem  2016; 91(5): 309-26.

[42]
Sowjanya C, Rao AR, Veeresham C. Pharmacokinetic and pharmacodynamic interaction of quercetin with saxagliptin in normal and diabetic rats. Pharmacol  2017; 8(3): 90-4.

[43]
Ahmad E, Jahangir M, Ishtiaq S, Haider HMF, Shah PA, Bukhari NI. Carbamazepine shows plasma and tissue pharmacokinetic interactions with Ajuga bracteosa extract in rats. Planta Medica Int Open  2021; 8(1): e10-8.
 [http://dx.doi.org/10.1055/a-1375-6570]

[44]
Mondal MIH, Yeasmin MS. Toxicity study of food-grade carboxymethyl cellulose synthesized from maize husk in Swiss albino mice. Int J Biol Macromol  2016; 92: 965-71.
 [http://dx.doi.org/10.1016/j.ijbiomac.2016.08.012] [PMID: 27506119]

[45]
Babu PR, Babu KN, Peter PLH, Rajesh K, Babu PJ. Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models. Drug Dev Ind Pharm  2013; 39(6): 873-9.
 [http://dx.doi.org/10.3109/03639045.2012.707209] [PMID: 22817837]

[46]
Challa S, Challa V, Ragam S. Quercetin declines plasma exposure of metoprolol tartrate in the rat model. J Adv Pharm Technol Res  2014; 5(4): 185-90.
 [http://dx.doi.org/10.4103/2231-4040.143038] [PMID: 25364697]

[47]
Choi JS, Han HK. The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. J Pharm Pharmacol  2010; 56(12): 1537-42.
 [http://dx.doi.org/10.1211/0022357044814] [PMID: 15563760]

[48]
Challa VR, Ravindra Babu P, Challa SR, Johnson B, Maheswari C. Pharmacokinetic interaction study between quercetin and valsartan in rats and in vitro models. Drug Dev Ind Pharm  2013; 39(6): 865-72.
 [http://dx.doi.org/10.3109/03639045.2012.693502] [PMID: 22670860]

[49]
Shapiro AB, Ling V. Effect of quercetin on hoechst 33342 transport by purified and reconstituted p-glycoprotein. Biochem Pharmacol  1997; 53(4): 587-96.
 [http://dx.doi.org/10.1016/S0006-2952(96)00826-X] [PMID: 9105411]

[50]
Choi JS, Piao YJ, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin. Arch Pharm Res  2011; 34(4): 607-13.
 [http://dx.doi.org/10.1007/s12272-011-0411-x] [PMID: 21544726]

[51]
Napagoda MT, Malkanthi BMAS, Abayawardana SAK, Qader MM, Jayasinghe L. Photoprotective potential in some medicinal plants used to treat skin diseases in Sri Lanka. BMC Complement Altern Med  2016; 16(1): 479.
 [http://dx.doi.org/10.1186/s12906-016-1455-8] [PMID: 27881112]

[52]
Benet L, Cummins C, Wu C. Transporter-enzyme interactions: Implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab  2003; 4(5): 393-8.
 [http://dx.doi.org/10.2174/1389200033489389] [PMID: 14529371]

[53]
Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem  1993; 62(1): 385-427.
 [http://dx.doi.org/10.1146/annurev.bi.62.070193.002125] [PMID: 8102521]

[54]
Gan LS, Moseley MA, Khosla B, et al. CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells. Drug Metab Dispos  1996; 24(3): 344-9.
 [PMID: 8820426]

[55]
Ito K, Kusuhara H, Sugiyama Y. Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach. Pharm Res  1999; 16(2): 225-31.
 [http://dx.doi.org/10.1023/A:1018872207437] [PMID: 10100307]

[56]
Watkins P. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev  1997; 27(2-3): 161-70.
 [http://dx.doi.org/10.1016/S0169-409X(97)00041-0] [PMID: 10837556]

[57]
Darvari R, Boroujerdi M. Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin — a comparison with tamoxifen. J Pharm Pharmacol  2010; 56(8): 985-91.
 [http://dx.doi.org/10.1211/0022357043941] [PMID: 15285842]

[58]
Martín-Algarra RV, Pascual-Costa RM, Merino M, Casabó VG. Intestinal absorption kinetics of amiodarone in rat small intestine. Biopharm Drug Dispos  1997; 18(6): 523-32.
 [http://dx.doi.org/10.1002/(SICI)1099-081X(199708)18:6<523::AID-BDD39>3.0.CO;2-2] [PMID: 9267684]

[59]
Amat N, Upur H, Blažeković B. In vivo hepatoprotective activity of the aqueous extract of Artemisia absinthium L. against chemically and immunologically induced liver injuries in mice. J Ethnopharmacol  2010; 131(2): 478-84.
 [http://dx.doi.org/10.1016/j.jep.2010.07.023] [PMID: 20637853]

[60]
Tariku Y, Hymete A, Hailu A, Rohloff J. In vitro evaluation of antileishmanial activity and toxicity of essential oils of Artemisia absinthium and Echinops kebericho. Chem Biodivers  2011; 8(4): 614-23.
 [http://dx.doi.org/10.1002/cbdv.201000331] [PMID: 21480507]

[61]
Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: A role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol  1992; 5(1): 54-9.
 [http://dx.doi.org/10.1021/tx00025a009] [PMID: 1581537]

[62]
Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther  1997; 73(1): 67-74.
 [http://dx.doi.org/10.1016/S0163-7258(96)00140-4] [PMID: 9014207]

[63]
Zhang Z, Fasco MJ, Huang Z, Guengerich FP, Kaminsky LS. Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos  1995; 23(12): 1339-46.
 [PMID: 8689941]

[64]
Huang W, Lin YS, McConn DJ II, et al. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos  2004; 32(12): 1434-45.
 [http://dx.doi.org/10.1124/dmd.104.001313] [PMID: 15383492]

[65]
Kang JM, Kim N, Kim B, et al. Gastroprotective action of Cochinchina momordica seed extract is mediated by activation of CGRP and inhibition of cPLA(2)/5-LOX pathway. Dig Dis Sci  2009; 54(12): 2549-60.
 [http://dx.doi.org/10.1007/s10620-008-0671-6] [PMID: 19130224]

[66]
Kim KA, Park PW, Kim HK, Ha JM, Park JY. Effect of quercetin on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy subjects. J Clin Pharmacol  2005; 45(8): 941-6.
 [http://dx.doi.org/10.1177/0091270005278407] [PMID: 16027405]

[67]
Shin S, Choi J, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm  2006; 313(1-2): 144-9.
 [http://dx.doi.org/10.1016/j.ijpharm.2006.01.028] [PMID: 16516418]

[68]
Nguyen MA, Staubach P, Wolffram S, Langguth P. Effect of single-dose and short-term administration of quercetin on the pharmacokinetics of talinolol in humans – Implications for the evaluation of transporter-mediated flavonoid–drug interactions. Eur J Pharm Sci  2014; 61: 54-60.
 [http://dx.doi.org/10.1016/j.ejps.2014.01.003] [PMID: 24472704]

[69]
Cermak R, Wein S, Wolffram S, Langguth P. Effects of the flavonol quercetin on the bioavailability of simvastatin in pigs. Eur J Pharm Sci  2009; 38(5): 519-24.
 [http://dx.doi.org/10.1016/j.ejps.2009.09.018] [PMID: 19804821]

[70]
Domingos AK, Saad EB, Vechiatto WWD, Wilhelm HM, Ramos LP. The influence of BHA, BHT and TBHQ on the oxidation stability of soybean oil ethyl esters (biodiesel). J Braz Chem Soc  2007; 18(2): 416-23.
 [http://dx.doi.org/10.1590/S0103-50532007000200026]

[71]
Chesebro J, Wiebers D, Holland A, et al. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med  1996; 156(4): 409-16.
 [http://dx.doi.org/10.1001/archinte.1996.00440040081009] [PMID: 8607726]

[72]
Yacobi A, Lai CM, Levy G. Comparative pharmacokinetics of coumarin anticoagulants XV: Relationship between pharmacokinetics of dicumarol and warfarin in rats. J Pharm Sci  1975; 64(12): 1995-8.
 [http://dx.doi.org/10.1002/jps.2600641220] [PMID: 54415]

[73]
Kivistö KT, Niemi M, Fromm MF. Functional interaction of intestinal CYP3A4 and P-glycoprotein. Fundam Clin Pharmacol  2004; 18(6): 621-6.
 [http://dx.doi.org/10.1111/j.1472-8206.2004.00291.x] [PMID: 15548232]

[74]
Shargel L. Biopharmaceutics. In: Encyclopedia of pharmaceutical science and technology.  (4th ed.). CRC Press: Florida 2013; pp. 195-210.

[75]
Levy G. Pharmacokinetics in renal disease. Am J Med  1977; 62(4): 461-5.
 [http://dx.doi.org/10.1016/0002-9343(77)90397-7]

Rights & Permissions Print Cite

Article Metrics

35

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574886317666221014101201	Print ISSN 1574-8863
Publisher Name Bentham Science Publisher	Online ISSN 2212-3911

Current Drug Safety

Influence of Quercetin Pretreatment on Pharmacokinetics of Warfarin in Rats

Abstract

Graphical Abstract

Related Journals

Related Books