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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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General Research Article

Evaluation of the Effects of Maytenus ilicifolia on the Activities of Cytochrome P450 3A and P-glycoprotein

Author(s): Sara Batista do Nascimento, Mariana de Lima Nascimento, Laís Lobato de Araújo, Flávio Martins de Oliveira, Maria do Carmo Vieira, Joaquim Maurício Duarte-Almeida, João Máximo Siqueira, Isabela da Costa César, Hartmut Derendorf and Whocely Victor de Castro*

Volume 21, Issue 4, 2020

Page: [281 - 290] Pages: 10

DOI: 10.2174/1389200221666200512112718

Price: $65

Abstract

Background: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown.

Objective: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities.

Methods: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI.

Results: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously.

Conclusion: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

Keywords: Maytenus ilicifolia, P-glycoprotein, cytochrome P4503A, herbal-drug interaction, Caco-2, midazolam.

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[1]
Organization, W.H. Traditional Medicine Strategy 2014-2023; World Health Organization: Geneve, 2013.
[2]
Smith, T.; Kawa, K.; Eckl, V.; Morton, C.; Stredney, R. Herbal supplement sales in US increased 8.5% in 2017, Topping $8 billion. HerbalGram, 2018, 2018(119), 62-71.
[3]
Garcia-Alvarez, A.; Egan, B.; de Klein, S.; Dima, L.; Maggi, F.M.; Isoniemi, M.; Ribas-Barba, L.; Raats, M.M.; Meissner, E.M.; Badea, M.; Bruno, F.; Salmenhaara, M.; Milà-Villarroel, R.; Knaze, V.; Hodgkins, C.; Marculescu, A.; Uusitalo, L.; Restani, P.; Serra-Majem, L. Usage of plant food supplements across six European countries: findings from the PlantLIBRA consumer survey. PLoS One, 2014, 9(3)e92265
[http://dx.doi.org/10.1371/journal.pone.0092265] [PMID: 24642692]
[4]
Oliveira, A.K.M.; Oliveira, N.A.; Resende, U.M.; Martins, P.F.R.B. Ethnobotany and traditional medicine of the inhabitants of the Pantanal Negro sub-region and the raizeiros of Miranda and Aquidauna, Mato Grosso do Sul, Brazil. Braz. J. Biol., 2011, 71(1)(Suppl. 1), 283-289.
[http://dx.doi.org/10.1590/S1519-69842011000200007] [PMID: 21537601]
[5]
Santos-Oliveira, R.; Coulaud-Cunha, S.; Colaço, W. Revisão da Maytenus ilicifolia Mart. ex. Reissek, Celestraceae. Contribuição no estudos das propriedades farmacológicas. Braz. J. Pharmacogn., 2009, 19(2B), 650-659.
[http://dx.doi.org/10.1590/S0102-695X2009000400025]
[6]
Tabach, R.; Duarte-Almeida, J.M.; Carlini, E.A. Pharmacological and toxicological study of Maytenus ilicifolia leaf extract part II - clinical study (Phase I). Phytother. Res., 2017, 31(6), 921-926.
[http://dx.doi.org/10.1002/ptr.5816] [PMID: 28480515]
[7]
Tarirai, C.; Viljoen, A.M.; Hamman, J.H. Herb-drug pharmacokinetic interactions reviewed. Expert Opin. Drug Metab. Toxicol., 2010, 6(12), 1515-1538.
[http://dx.doi.org/10.1517/17425255.2010.529129] [PMID: 21067427]
[8]
Zhou, S.; Lim, L.Y.; Chowbay, B. Herbal modulation of P-glycoprotein. Drug Metab. Rev., 2004, 36(1), 57-104.
[http://dx.doi.org/10.1081/DMR-120028427] [PMID: 15072439]
[9]
de Wildt, S.N.; Kearns, G.L.; Leeder, J.S.; van den Anker, J.N. Cytochrome P450 3A: ontogeny and drug disposition. Clin. Pharmacokinet., 1999, 37(6), 485-505.
[http://dx.doi.org/10.2165/00003088-199937060-00004] [PMID: 10628899]
[10]
Lin, J.H.; Yamazaki, M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin. Pharmacokinet., 2003, 42(1), 59-98.
[http://dx.doi.org/10.2165/00003088-200342010-00003] [PMID: 12489979]
[11]
Parvez, M.K.; Rishi, V. Herb-drug interactions and hepatotoxicity. Curr. Drug Metab., 2019, 20(4), 275-282.
[http://dx.doi.org/10.2174/1389200220666190325141422] [PMID: 30914020]
[12]
Bjornsson, T.D.; Callaghan, J.T.; Einolf, H.J.; Fischer, V.; Gan, L.; Grimm, S.; Kao, J.; King, S.P.; Miwa, G.; Ni, L.; Kumar, G.; McLeod, J.; Obach, S.R.; Roberts, S.; Roe, A.; Shah, A.; Snikeris, F.; Sullivan, J.T.; Tweedie, D.; Vega, J.M.; Walsh, J.; Wrighton, S.A. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J. Clin. Pharmacol., 2003, 43(5), 443-469.
[http://dx.doi.org/10.1177/0091270003252519] [PMID: 12751267]
[13]
FDA. Guidance for Industry: Drug Interactions Studies - Study Design, Data Analysis, and Clinical Implications, 2017. Available at:, https://www.fda.gov/files/drugs/published/Clinical-Drug-Interaction-Studies-%E2%80%94-Study-Design--Data-Analysis--and-Clinical-Implications-Guidance-for-Industry.pdf
[14]
Togami, K.; Tosaki, Y.; Chono, S.; Morimoto, K.; Hayasaka, M.; Tada, H. Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal epithelial cells. J. Pharm. Pharmacol., 2013, 65(1), 22-29.
[http://dx.doi.org/10.1111/j.2042-7158.2012.01569.x] [PMID: 23215684]
[15]
Bentz, J.; O’Connor, M.P.; Bednarczyk, D.; Coleman, J.; Lee, C.; Palm, J.; Anne Pak, Y.; Perloff, E.S.; Reyner, E.; Balimane, P.; Brännström, M.; Chu, X.; Funk, C.; Guo, A.; Hanna, I.; Herédi-Szabó, K.; Hillgren, K.; Li, L.; Hollnack-Pusch, E.; Jamei, M.; Lin, X.; Mason, A.K.; Neuhoff, S.; Patel, A.; Podila, L.; Plise, E.; Rajaraman, G.; Salphati, L.; Sands, E.; Taub, M.E.; Taur, J.S.; Weitz, D.; Wortelboer, H.M.; Xia, C.Q.; Xiao, G.; Yabut, J.; Yamagata, T.; Zhang, L.; Ellens, H. Variability in P-glycoprotein inhibitory potency (IC50) using various in vitro experimental systems: implications for universal digoxin DDI risk assessment decision criteria. Drug Metab. Dispos., 2013, 41, 1347-1366.
[http://dx.doi.org/10.1124/dmd.112.050500] [PMID: 23620485]
[16]
Zeller, W.; Weber, H.; Panoussis, B.; Bürge, T.; Bergmann, R. Refinement of blood sampling from the sublingual vein of rats. Lab. Anim., 1998, 32(4), 369-376.
[http://dx.doi.org/10.1258/002367798780599910] [PMID: 9807750]
[17]
Kimura, Y.; Ito, H.; Ohnishi, R.; Hatano, T. Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity. Food Chem. Toxicol., 2010, 48(1), 429-435.
[http://dx.doi.org/10.1016/j.fct.2009.10.041] [PMID: 19883715]
[18]
Eid, S.Y.; El-Readi, M.Z.; Eldin, E.E.M.N.; Fatani, S.H.; Wink, M. Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells. Phytomedicine, 2013, 21(1), 47-61.
[http://dx.doi.org/10.1016/j.phymed.2013.07.019] [PMID: 23999162]
[19]
Wei, J.; Zhang, H.; Zhao, Q. In vitro inhibitory effects of Friedelin on human liver cytochrome P450 enzymes. Pharm. Biol., 2018, 56(1), 363-367.
[http://dx.doi.org/10.1080/13880209.2018.1491999] [PMID: 30122094]
[20]
Yu, C.P.; Huang, C.Y.; Lin, S.P.; Hou, Y.C. Activation of Pglycoprotein and CYP 3A by coptidis rhizoma in vivo: using cyclosporine as a probe substrate in rats. Yao Wu Shi Pin Fen Xi, 2018, 26(2S), S125-S132.
[http://dx.doi.org/10.1016/j.jfda.2017.11.005] [PMID: 29703381]
[21]
Liu, C.; Yi, X.; Si, D.; Xiao, X.; He, X.; Li, Y. Herb-drug interactions involving drug metabolizing enzymes and transporters. Curr. Drug Metabol., 2011, 835-849.
[http://dx.doi.org/10.2174/138920011797470083]
[22]
Andrade, R.A.M.S.; Maciel, M.I.S.; Santos, A.M.P.; Melo, E.A. Optimization of the extraction process of polyphenols from cashew apple agro-industrial residues. Food Sci. Technol., 2015, 35(2), 354-360.
[http://dx.doi.org/10.1590/1678-457X.6585]
[23]
Martins, P.M.; Lanchote, A.D.; Thorat, B.N.; Freitas, L.A.P. Turbo-extraction of glycosides from Stevia rebaudiana using a fractional factorial design. Braz. J. Pharmacog., 2017, 27, 510-518.
[http://dx.doi.org/10.1016/j.bjp.2017.02.007]
[24]
Guyot, S.; Marnet, N.; Drilleau, J. Thiolysis-HPLC characterization of apple procyanidins covering a large range of polymerization states. J. Agric. Food Chem., 2001, 49(1), 14-20.
[http://dx.doi.org/10.1021/jf000814z] [PMID: 11170553]
[25]
Cunha-Laura, A.L.; Auharek, S.A.; Oliveira, R.J.; Siqueira, J.M.; Vieira, M.C.M.C.; Leite, V.S.; Portugal, L.C. Effects of Maytenus ilicifolia on reproduction and embryo-fetal development in Wistar rats. Genet. Mol. Res., 2014, 13(2), 3711-3720.
[http://dx.doi.org/10.4238/2014.May.9.16] [PMID: 24854657]
[26]
Piazza, S.; Pacchetti, B.; Fumagalli, M.; Bonacina, F.; Dell’Agli, M.; Sangiovanni, E. Comparison of two Ginkgo biloba L. extracts on oxidative stressm and inflammation markers in human endothelial cells. Mediators Inflamm., 2019, 20196173893
[http://dx.doi.org/10.1155/2019/6173893] [PMID: 31341420]
[27]
Clostre, F. Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year 2000. Ann. Pharm. Fr.,, 1999,, 57(Suppl 1),, 1S8-- 88..
[28]
Akamine, Y.; Yasui-Furukori, N.; Uno, T. Drug-drug interaction of P-gp substrates unrelated to CYP metabolism. Curr. Drug Metab., 2019, 20(2), 124-129.
[http://dx.doi.org/10.2174/1389200219666181003142036] [PMID: 30280663]
[29]
Awortwe, C.; Fasinu, P.S.; Rosenkranz, B. Application of Caco-2 cell line in herb-drug interaction studies: current approaches and challenges. J. Pharm. Pharm. Sci., 2014, 17(1), 1-19.
[http://dx.doi.org/10.18433/J30K63] [PMID: 24735758]
[30]
Volpe, D.A. Drug-permeability and transporter assays in Caco-2 and MDCK cell lines. Future Med. Chem., 2011, 3(16), 2063-2077.
[http://dx.doi.org/10.4155/fmc.11.149] [PMID: 22098353]
[31]
Brück, S.; Strohmeier, J.; Busch, D.; Drozdzik, M.; Oswald, S. Caco-2 cells - expression, regulation and function of drug transporters compared with human jejunal tissue. Biopharm. Drug Dispos., 2017, 38(2), 115-126.
[http://dx.doi.org/10.1002/bdd.2025] [PMID: 27516347]
[32]
Fox, E.; Bates, S.E. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev. Anticancer Ther., 2007, 7(4), 447-459.
[http://dx.doi.org/10.1586/14737140.7.4.447] [PMID: 17428165]
[33]
Mudie, D.M.; Murray, K.; Hoad, C.L.; Pritchard, S.E.; Garnett, M.C.; Amidon, G.L.; Gowland, P.A.; Spiller, R.C.; Amidon, G.E.; Marciani, L. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol. Pharm., 2014, 11(9), 3039-3047.
[http://dx.doi.org/10.1021/mp500210c] [PMID: 25115349]
[34]
Dillard, R.L.; Eastman, H.; Fordtran, J.S. Volume-flow relationship during the transport of fluid though human small intestine. Gastroenterology, 1965, 49, 58-66.
[http://dx.doi.org/10.1016/S0016-5085(19)34581-0]
[35]
Niero, R.; de Andrade, S.F.; Cechinel Filho, V. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus genus. Curr. Pharm. Des., 2011, 17(18), 1851-1871.
[http://dx.doi.org/10.2174/138161211796391029] [PMID: 21554223]
[36]
Tiberti, L.A.; Yariwake, J.H.; Ndjoko, K.; Hostettmann, K. Identification of flavonols in leaves of Maytenus ilicifolia and M. aquifolium (Celastraceae) by LC/UV/MS analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2007, 846(1-2), 378-384.
[http://dx.doi.org/10.1016/j.jchromb.2006.09.014] [PMID: 17011840]
[37]
Leite, V.J.P.; Braga, F.C.; Romussi, G.; Persoli, R.M.; Tabach, R.; Carlini, E.A.; Oliveira, A.B. Constituents from Maytenus ilicifolia leaves and bioguided fractionation for gastroprotective activity. J. Braz. Chem. Soc., 2010, 21(10), 248-254.
[http://dx.doi.org/10.1590/S0103-50532010000200009]
[38]
Pedrosa, A.M.; Siqueira, J.M.; Vieira, M.C.; Duarte-Almeida, J.M. Avaliação de diferentes extratos de Maytenus ilicifolia: teores de metabólitos secundários e perfil cromatográfico In: Plantas medicinais: os avanços das pesquisas no século XXI, 1st ed.; Sousa,B.J.M.; Alves, B.C.; Duarte-Almeida, J.M., Eds.; Gulliver: Divinópolis,; , 2018;, pp. 75-- 87..
[39]
Mohana, S.; Ganesan, M.; Agilan, B.; Karthikeyan, R.; Srithar, G.; Beaulah Mary, R.; Ananthakrishnan, D.; Velmurugan, D.; Rajendra Prasad, N.; Ambudkar, S.V. Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer. Mol. Biosyst., 2016, 12(8), 2458-2470.
[http://dx.doi.org/10.1039/C6MB00187D] [PMID: 27216424]
[40]
Kim, K.A.; Park, P.W.; Park, J.Y. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur. J. Clin. Pharmacol., 2009, 65(6), 609-614.
[http://dx.doi.org/10.1007/s00228-009-0627-6] [PMID: 19221726]
[41]
Lee, J.A.; Ha, S.K.; Kim, Y.C.; Choi, I. Effects of friedelin on the intestinal permeability and bioavailability of apigenin. Pharmacol. Rep., 2017, 69(5), 1044-1048.
[http://dx.doi.org/10.1016/j.pharep.2017.04.012] [PMID: 28939344]
[42]
Mandery, K.; Bujok, K.; Schmidt, I.; Keiser, M.; Siegmund, W.; Balk, B.; König, J.; Fromm, M.F.; Glaeser, H. Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem. Pharmacol., 2010, 80(11), 1746-1753.
[http://dx.doi.org/10.1016/j.bcp.2010.08.008] [PMID: 20797388]
[43]
Butterweck, V.; Derendorf, H.; Gaus, W.; Nahrstedt, A.; Schulz, V.; Unger, M. Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate? Planta Med., 2004, 70(9), 784-791.
[http://dx.doi.org/10.1055/s-2004-827223] [PMID: 15386186]
[44]
Kitagawa, S.; Nabekura, T.; Nakamura, Y.; Takahashi, T.; Kashiwada, Y. Inhibition of P-glycoprotein function by tannic acid and pentagalloylglucose. J. Pharm. Pharmacol., 2007, 59(7), 965-969.
[http://dx.doi.org/10.1211/jpp.59.7.0008] [PMID: 17637191]
[45]
Li, H.; Krstin, S.; Wink, M. Modulation of multidrug resistant in cancer cells by EGCG, tannic acid and curcumin. Phytomedicine, 2018, 50(50), 213-222.
[http://dx.doi.org/10.1016/j.phymed.2018.09.169] [PMID: 30466981]
[46]
Wonfor, R.; Natoli, M.; Parveen, I.; Beckman, M.; Nash, R.; Nash, D. Anti-inflammatory properties of an extract of M. ilicifolia in the human intestinal epithelial Caco-2 cell line. J. Ethnopharmacol., 2017, 209, 283-287.
[http://dx.doi.org/10.1016/j.jep.2017.08.006] [PMID: 28789861]
[47]
Kupferschmidt, H.H.; Ha, H.R.; Ziegler, W.H.; Meier, P.J.; Krähenbühl, S. Interaction between grapefruit juice and midazolam in humans. Clin. Pharmacol. Ther., 1995, 58(1), 20-28.
[http://dx.doi.org/10.1016/0009-9236(95)90068-3] [PMID: 7628179]
[48]
Lundahl, J.; Regårdh, C.G.; Edgar, B.; Johnsson, G. Effects of grapefruit juice ingestion--pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur. J. Clin. Pharmacol., 1997, 52(2), 139-145.
[http://dx.doi.org/10.1007/s002280050263] [PMID: 9174684]
[49]
Basheer, L.; Kerem, Z. Interactions between CYP3A4 and dietary polyphenols. Oxid. Med. Cell. Longev., 2015, 2015854015
[http://dx.doi.org/10.1155/2015/854015] [PMID: 26180597]
[50]
Nishimuta, H.; Nakagawa, T.; Nomura, N.; Yabuki, M. Species differences in hepatic and intestinal metabolic activities for 43 human cytochrome P450 substrates between humans and rats or dogs. Xenobiotica, 2013, 43(11), 948-955.
[http://dx.doi.org/10.3109/00498254.2013.787155] [PMID: 23593983]
[51]
Rocha, J.N.; Johansson, L.A.P.S.; Miranda, L.V.; Lopes, G.C.; Diniz, A.; Mello, J.C.P.; Souza, J.R.P. Desenvolvimento de Maytenus ilicifolia e de seus polifenóis totais sob condição de sombreamento e poda. Rev. Bras. Pl. Med., 2014, 16(3)(Suppl. I), 663-669.
[52]
Anadón, A.; Martínez, M.A.; Castellano, V.; Martínez-Larrañaga, M.R. The role of in vitro methods as alternatives to animals in toxicity testing. Expert Opin. Drug Metab. Toxicol., 2014, 10(1), 67-79.
[http://dx.doi.org/10.1517/17425255.2014.854329] [PMID: 24160258]
[53]
Salyers, K.L.; Xu, Y. Animal models for studying drug metabolizing enzymes and transporters.. In: ADME-enabling technologies in drug design and development, 1st ed.; Zhang, H.; Surapaneni, S., Eds.;; Jonh Wiley & Sons Inc.:: New Jersy,, 2012,, p. p. 622..
[http://dx.doi.org/10.1002/9781118180778.ch16]
[54]
Chung, S.Y.; Sung, M.K.; Kim, N.H.; Jang, J.O.; Go, E.J.; Lee, H.J. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch. Pharm. Res., 2005, 28(7), 823-828.
[http://dx.doi.org/10.1007/BF02977349] [PMID: 16114498]
[55]
Bhardwaj, R.K.; Glaeser, H.; Becquemont, L.; Klotz, U.; Gupta, S.K.; Fromm, M.F. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther., 2002, 302(2), 645-650.
[http://dx.doi.org/10.1124/jpet.102.034728] [PMID: 12130727]
[56]
Hennessy, M.; Kelleher, D.; Spiers, J.P.; Barry, M.; Kavanagh, P.; Back, D.; Mulcahy, F.; Feely, J. St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br. J. Clin. Pharmacol., 2002, 53(1), 75-82.
[http://dx.doi.org/10.1046/j.0306-5251.2001.01516.x] [PMID: 11849198]
[57]
Lown, K.S.; Bailey, D.G.; Fontana, R.J.; Janardan, S.K.; Adair, C.H.; Fortlage, L.A.; Brown, M.B.; Guo, W.; Watkins, P.B. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J. Clin. Invest., 1997, 99(10), 2545-2553.
[http://dx.doi.org/10.1172/JCI119439] [PMID: 9153299]
[58]
Moore, L.B.; Goodwin, B.; Jones, S.A.; Wisely, G.B.; Serabjit-Singh, C.J.; Willson, T.M.; Collins, J.L.; Kliewer, S.A. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad. Sci. USA, 2000, 97(13), 7500-7502.
[http://dx.doi.org/10.1073/pnas.130155097] [PMID: 10852961]

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