Theoretical perspectives on the interaction between warfarin and garlic compounds with an in silico study of CYP3A4
DOI:
https://doi.org/10.5902/2236583436133Keywords:
S-allyl-L-cysteine, S-methyl-L-cysteine, S-allylmercaptocysteine, Allium sativum L., warfarin, CYP3A4Abstract
Garlic (Allium sativum L.) is one of the most consumed food supplements in the world and has multiple biological properties. Among all molecules obtained from garlic, S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC) and S-allylmercaptocysteine (SAMC) are highlighted. There are in vitro and in vivo studies which correlate the interactions of these molecules with medicinal drugs such as warfarin by competition site in the cytochrome P450 isoenzymes (CYP). Warfarin is an oral anticoagulant belong to vitamin K antagonist class and metabolized by CYP 3A4, 2C9 and 2C19. This article consists in a review showing studies with extracts and/or isolated garlic compounds, metabolic pathways and biological consequences considering drug interactions. The results revealed that garlic extracts express an inhibitory activity in CYP 3A4, 2C9 and 2C19. Inhibition of CYP3A4 were greater than 50% for SAC and SAMC. In silico experiment was performed for SAC, SMC and SAMC in the CYP3A4 isoenzyme which SAMC showed lower energy of interaction (-85.9 Kcal mole-1). (R)-warfarin was docked in same molecular cavity from this active site and showed lower value of energy interaction (-101.1 Kcal mole-1) in comparison with three compounds, which may suggest the warfarin showed better affinity with CYP3A4. Consequently, SAMC interacts better with CYP3A4, followed by SAC and SMC (-80.4 and -70.2 Kcal mole-1, respectively). These results indicate the mercaptocysteine shows better fit with the active site of human CYP3A4. So, these interactions may potentiate the risk of bleeding in patients during warfarin therapy, because some of the garlic compounds inhibit the CYP enzymes responsible for the biotransformation of (R)-warfarin. These findings suggest the consume of garlic should be monitored in patients receiving warfarin therapy and health professionals must be aware of this interaction.
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Sposito, Ac, Caramelli, B, Fonseca, Fah, Bertolami, MC. IV Diretriz Brasileira sobre Dislipidemias e Prevenção da Aterosclerose: Departamento de Aterosclerose da Sociedade Brasileira de Cardiologia. Arq. Bras. Cardiol., São Paulo, v. 88, supl. 1, p. 2-19, Apr. 2007.
Wysowski, Dk, Nourjah, P, Swartz, L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Archives of internal medicine, v. 167, n. 13, p. 1414–9, 2007.
Bonar, R, Favaloro, EJ. Explaining and reducing the variation in inter-laboratory reported values for International Normalized Ratio. Thrombosis Research, v. 150, p. 22–29, 2017.
Zhou, S, Gao, Y, Jiang, W, Huang, M, Xu, A, Paxton, JW. Interactions of herbs with cytochrome P450. Drug Metabolism Reviews, v. 35, n. 1, p. 35–98, 2003.
Butterweck, V, Derendorf, H. Potential of Pharmacokinetic Profiling for Detecting Herbal Interactions with Drugs. Clinical Pharmacokinetics, v. 47, n. 6, p. 383–397, 2008.
Kieffer J, Bremond E, Lienard P, Boccardi G. In silico assessment of drug substances chemical stability. J Mol Struc Theochem. 2010;954(1-3):75-79
Singh, VK, Singh, DK. ARBS Annual Review of Biomedical Sciences Pharmacological Effects of Garlic (Allium sativum L.). ARBS Annual Review of Biomedical Sciences, p. 6–26, 2008.
Chen, X-W, B. Sneed, KB, Pan, S-Y et al. Herb-Drug Interactions and Mechanistic and Clinical Considerations. Current Drug Metabolism, v. 13, n. 5, p. 640–651, 2012.
Bayan, L, Koulivand, Ph, Gorji, A. Garlic: a review of potential therapeutic effects. Avicenna journal of phytomedicine, v. 4, n. 1, p. 1–14, 2014.
Khatua, TN, Adela, R, Banerjee, SK. Garlic and cardioprotection: insights into the molecular mechanisms. Canadian Journal of Physiology and Pharmacology, v. 91, n. 6, p. 448–458, 2013.
Kiesewetter, H, Jung, F, Jung, Em, Mrowietz, C, Koscielny, J, Wenzel, E. Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. European Journal of Clinical Pharmacology, v. 45, n. 4, p. 333–336, 1993.
Bordia, A, Verma, SK, Srivastava, KC. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukotrienes and Essential Fatty Acids, v. 58, n. 4, p. 257–263, 1998.
Mikaili, P, Maadirad, S, Moloudizargari, M, Aghajanshakeri, S, Sarahroodi, S. Therapeutic uses and pharmacological properties of garlic, shallot, and their biologically active compounds. Iranian Journal of Basic Medical Sciences, v. 16, n. 10, p. 1031–1048, 2013.
Saeidnia, S, Manayi, A, Abdollahi, M. The Pros and Cons of the In-silico Pharmaco-toxicology in Drug Discovery and Development. International Journal of Pharmacology, v. 9, n. 3, p. 176–181, 2013.
Carvalho I, PMT, Borges ADL, Bernardes LSC. Introdução à modelagem molecular de fármacos no curso experimental de química farmacêutica. Quim Nova 2003;26(3):428-438.
Kaur, P, Chamberlin, AR, Poulos, TL, Sevrioukova, IF. Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model. Journal of Medicinal Chemistry, v. 59, n. 9, p. 4210–4220, 2016.
Berman, HM, Westbrook, J, Feng, Z, et al. The Protein Data Bank Helen. Nucleic acids research, v. 28, n. 1, p. 235–242, 2000.
Morris, GM, Huey, R, Lindstrom, W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, v. 30, n. 16, p. 2785–2791, 2009.
Yang, JM; Chen, CC. GEMDOCK: A Generic Evolutionary Method for Molecular Docking. Proteins: Structure, Function and Genetics, v. 55, n. 2, p. 288–304, 2004.
Mittal, B, Tulsyan, S, Kumar, S, Mittal, RD, Agarwal, G. Cytochrome P450 in Cancer Susceptibility and Treatment. 1. ed. [s.l.]: Elsevier Inc., 2015.
Guengerich, FP. Cytochrome P450s and other enzymes in drug metabolism and toxicity. The AAPS Journal, v. 8, n. 1, p. E101–E111, 2006.
Zeng, T, Xie, KQ. The differential modulation on cytochrome P450 enzymes by garlic components. Food Reviews International, v. 26, n. 4, p. 353–363, 2010.
De Graaf, C, Vermeulen, NPE, Feenstra, KA. Cytochrome p450 in silico: an integrative modeling approach. Journal of medicinal chemistry, v. 48, n. 8, p. 2725–55, 2005.
Foster, BC, Vandenhoek, S, Hana, J, et al. In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products. Phytomedicine: international journal of phytotherapy and phytopharmacology, v. 10, n. 4, p. 334–42, 2003.
Chin, AC; Baskin, LB. Effect of Herbal Supplement–Drug Interactions on Therapeutic Drug Monitoring. In: Therapeutic Drug Monitoring. [s.l.]: Elsevier, 2012, p. 417–445.
Nembri, S, Grisoni, F, Consonni, V, Todeschini, R. In Silico prediction of cytochrome P450-drug interaction: QSARs for CYP3a4 and CYP2C9. International Journal of Molecular Sciences, v. 17, n. 6, 2016.
Kaserer, T, Höferl, M, Müller, K, et al. In Silico Predictions of Drug - Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition - A Comparative Study of Virtual Screening Performance. Molecular Informatics, v. 34, n. 6–7, p. 431–457, 2015.
Margolis, JM, O'donnell, JP, Mankowski, DC, Ekins, S, Obach, RS. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug metabolism and disposition: the biological fate of chemicals, v. 28, n. 10, p. 1187–91, 2000.
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. Chemical Research in Toxicology, v. 5, n. 1, p. 54–59, 1992.
Tracy, TS; Marra, C; Wrighton, SA, Gonzales, FJ, Korzekwa, R. Studies of Flurbiprofen. v. 52, n. 96, p. 1305–1309, 1996
Miners, J, Coulter, S, Tukey, RH, Veronese, ME, Birkett, DJ. Cytochromes P450, 1A2, and 2C9 are Responsible for the Human Hepatic O-Demethylation of R * and S-Naproxen. Science, v. 51, n. June 1995, p. 1003–1008, 1996.
Scripture, CD, Pieper, JA. Clinical pharmacokinetics of fluvastatin. Clinical Pharmacokinetics, v. 40, n. 4, p. 263–281, 2001.
Tang, W. The metabolism of diclofenac--enzymology and toxicology perspectives. Current drug metabolism, v. 4, n. 4, p. 319–29, 2003.
Chang, S-Y, Li, W, Traeger, SC. et al. Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. Drug Metabolism and Disposition, v. 36, n. 12, p. 2513–2522, 2008.
Wu, J-J, Ai, C-Z, Liu, Y et al. Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes. Current Drug Metabolism, v. 13, n. 5, p. 599–614, 2012.
Guengerich, FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annual review of pharmacology and toxicology, v. 39, n. 1, p. 1–17, 1999.
Zhang, Y-Y, Yang, L. Interactions between human cytochrome P450 enzymes and steroids: physiological and pharmacological implications. Expert opinion on drug metabolism & toxicology, v. 5, n. 6, p. 621–9, 2009.
Kudo, S, Okumura, H, Miyamoto, G, Ishizaki, T. Cytochrome P-450 Isoforms Involved in Carboxylic Acid Ester Cleavage of Hantzsch Pyridine Ester of Pranidipine. Drug Metabolism and Disposition, v. 27, n. 2, p. 303 LP-308, 1999.
Zhang, Z, Li, Y, Stearns, RA, Montellano, PRO, Baillie, TA, Tang, W. Cytochrome P450 3A4-mediated oxidative conversion of a cyano to an amide group in the metabolism of pinacidil. Biochemistry, v. 41, n. 8, p. 2712–2718, 2002.
Bodin, K, Andersson, U, Rystedt, E, et al. Metabolism of 4β-hydroxycholesterol in humans. Journal of Biological Chemistry, v. 277, n. 35, p. 31534–31540, 2002.
Kronbach T, Fischer V, Meyer UA. Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs Clin Pharmacol Ther 43:630–635, 1988.
Wang, RW, Kari, PH, Lu, AY, Thomas, PE, Guengerich, FP, Vyas, KP. Biotransformation of lovastatin IV Identification of cytochrome P4503A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 290:355–361, 1991.
Huskey, SW, Dean, DC, Miller, RR, Rasmusson, GH, Chiu, SH. Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride. Drug Metab Dispos 23:1126–1135, 1995.
Koudriakova, T, Iatsimirskaia E, Utkin, I. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir Drug Metab Dispos 26:552–561, 1998.
Warrington, JS, Shader, RI, Von Moltke, LL, Greenblatt, DJ. In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos 28:392–397, 2000.
Bodin, K, Bretillon, L, Aden, Y et al. Antiepileptic drugs increase plasma levels of 4β- hydroxycholesterol in humans: evidence for involvement of cytochrome P450 3A4. J Biol Chem 276:38685–38689, 2001.
Weitz, JI. Coagulação sanguínea e fármacos anticoagulantes, fibrinolíticos e antiplaquetários. In: BRUNTON, LL, CHABNER, BA, KNOLLMANN, BC, autores. As Bases Farmacológicas de Goodman & Gilman. 12° Ed. Porto Alegre: AMGH; 2012. p. 849-876.
Abhaykumar, Nirmala, K, Prasad, MPR, et al. Reduction in Platelet Aggregation (in vitro) by Diallyl Sulphide in Female Participants with Type 2 Diabetes Mellitus. Journal of Pharmacology and Toxicology, v. 6, n. 4, p. 381–390, 2011.
Broos, K, Feys, HB, De Meyer, SF, Vanhoorelbeke, K, Deckmyn, H. Platelets at work in primary hemostasis. Blood Reviews, v. 25, n. 4, p. 155–167, 2011.
Jobling, L, Eyre, L. Haemostasis, blood platelets and coagulation. Anaesthesia and Intensive Care Medicine, v. 14, n. 2, p. 51–53, 2013.
Rogers, HJ, Nakashima, MO, Kottke-Marchant, K. Hemostasis and Thrombosis. In: HSI, Eric D B T – Hematopathology. 3° Ed. Philadelphia: Elsevier; 2018. p. 57–105.e4.
Chaves, DSA, Costa, SS, Almeida, AP, Frattani, F, Assafim, M, Zingali, RB. Metabólitos secundários de origem vegetal: Uma fonte potencial de fármacos antitrombóticos. Química Nova, v. 33, n. 1, p. 172–180, 2010.
Chapin, JC, Hajjar, KA. Fibrinolysis and the control of blood coagulation John NIH Public Access. v. 29, n. 1, p. 17–24, 2015.
Zehnder, JL. Fármacos usados nos distúrbios da coagulação. In: KATZUNG, BG, MASTERS, SB, TREVOR, AJ. Farmacologia Básica e Aplicada. Porto Alegre: AMGH, 12° Ed., 2014, p. 601-618.
Müller, E, Keller, A, Fregin, A, Müller, CR, Rost, S. Confirmation of warfarin resistance of naturally occurring VKORC1 variants by coexpression with coagulation factor IX and in silico protein modelling. BMC genetics, v. 15, n. 1, p. 17, 2014.
Nadkarni, A, Oldham, MA, Howard, M, Berenbaum, I. Drug-drug interactions between warfarin and psychotropics: Updated review of the literature. Pharmacotherapy, v. 32, n. 10, p. 932–942, 2012.;
Di Minno, A, Frigerio, B, Spadarella, G, et al. Old and new oral anticoagulants: Food, herbal medicines and drug interactions. Blood Reviews, 2017
Oates, JA, Wood, AJJ, Hirsh, J. Oral Anticoagulant Drugs. New England Journal of Medicine, v. 324, n. 26, p. 1865–1875, 1991.
Holford, NH. Clinical pharmacokinetics and pharmacodynamics of warfarin. Clin Pharmacokinet, v. 11, n. 6, p. 483–504, 1986.
Dewald, TA, Washam, JB, Becker, RC. Anticoagulants: Pharmacokinetics, Mechanisms of Action, and Indications. Neurosurgery Clinics of North America, v. 29, n. 4, p. 503–515, 2018.
HOSPITAL DE CLÍNICAS DE PORTO ALEGRE HCPA, Protocolo Assistencial Anticoagulação Oral, PRT-0008. Hospital de Clinicas de Porto Alegre, RS - 2012.
Macan, H, Uykimpang, R, Alconcel, M, et al. Aged garlic extract may be safe for patients on warfarin therapy. The Journal of Nutrition, 136, 793Se795S, 2006.
Ho, BE, Shen, DD, McCune, JS et al. Effects of Garlic on Cytochromes P450 2C9- and 3A4-Mediated Drug Metabolism in Human Hepatocytes. Scientia Pharmaceutica. v. 78, n. 3, p. 473-481, 2010.
Schäfer, G, Kaschula, CH. The immunomodulation and anti-inflammatory effects of garlic organosulfur compounds in cancer chemoprevention. Anti-cancer agents in medicinal chemistry, v. 14, n. 2, p. 233–40, 2014.
Reuter, HD, Koch, HP, Lawson, LD. Therapeutic effects and applications of garlic and its preparations. In H. P. Koch, & L. D. Lawson (Eds.), Garlic, the science and therapeutic application of Allium sativum L. and related species (pp. 135e213). Baltimore: Williams and Wilkins, 1996.
Ried, K, Fakler, P. Potential of garlic (Allium sativum) in lowering high blood pressure: Mechanisms of action and clinical relevance. Integrated Blood Pressure Control, v. 7, p. 71–82, 2014.
Ramadan, G, El-Beih, NM, Ahmed, RS. Aged garlic extract ameliorates immunotoxicity, hematotoxicity and impaired burn-healing in malathion- and carbaryl-treated male albino rats. Environmental Toxicology, v. 32, n. 3, p. 789-798, 2017.
Lanzotti, V. The analysis of onion and garlic. Journal of Chromatography A, v. 1112, n. 1–2, p. 3–22, 21 abr. 2006.
Corzo-Martínez, M, Corzo, N, Villamiel, M. Biological properties of onions and garlic. Trends in Food Science and Technology, v. 18, n. 12, p. 609–625, 2007.
Chen, X-W, Serag, ES, Sneed, KB, et al. Clinical Herbal Interactions with Conventional Drugs: From Molecules to Maladies. Current Medicinal Chemistry, v. 18, n. 31, p. 4836–4850, 2011.
Rahman, K. Effects of garlic on platelet biochemistry and physiology. Molecular Nutrition and Food Research, v. 51, n. 11, p. 1335–1344, 2007.
Chan, JY-Y, Yuen, AC-Y, Chan, RY-K; Chan, S-W. A review of the cardiovascular benefits and antioxidant properties of allicin. Phytotherapy Research, v. 646, n. June 2012, p. 637–747, 2013.
Moutia, M, Habti, N, Badou, A. In Vitro and In Vivo Immunomodulator Activities of Allium sativum L. Evidence-Based Complementary and Alternative Medicine, v. 2018, n. 5, p. 1–10, 2018.
Lawson, LD, Wang, ZJ. Allicin and allicin-derived garlic compounds increase breath acetone through allyl methyl sulfide: Use in measuring allicin bioavailability. Journal of Agricultural and Food Chemistry, v. 53, n. 6, p. 1974–1983, 2005
Gao, C, Jiang, X, Wang, H, Zhao, Z, Wang, W. Drug Metabolism and Pharmacokinetics of Organosulfur Compounds from Garlic. Journal of Drug Metabolism & Toxicology, v. 04, n. 05, p. 1–10, 2013.
Morihara, N, Hino, A. Aged garlic extract suppresses platelet aggregation by changing the functional property of platelets. Journal of Natural Medicines, v. 71, n. 1, p. 249–256, 2017.
National Center for Biotechnology Information. PubChem Compound Database; CID=9794159. [citado em 2018 Out 10]. Disponível em: https://pubchem.ncbi.nlm.nih.gov/compound/9794159.
National Center for Biotechnology Information. PubChem Compound Database; CID=9793905. [citado em 2018 Out 10]. Disponível em: https://pubchem.ncbi.nlm.nih.gov/compound/9793905.
National Center for Biotechnology Information. PubChem Compound Database; CID=24417. [citado em 2018 Out 10]. Disponível em: https://pubchem.ncbi.nlm.nih.gov/compound/24417.
Chemicalize. ChemAxon. Instant Cheminformatics solutions; 1998-2018. [citado em 2018 Set 20]. Disponível em https://chemicalize.com/.
Tsai, CW, Lin, H-W, Lu, Y-H, Chen, Y-L, Mahady, GB. Garlic: Health benefits and actions. BioMedicine (Netherlands), v. 2, n. 1, p. 17–29, 2012.
Vaes, LPJ, Chyka, PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: Nature of the evidence. Annals of Pharmacotherapy, v. 34, n. 12, p. 1478–1482, 2000.
Shi, S, Klotz, U. Drug interactions with herbal medicines. Clinical Pharmacokinetics, v. 51, n. 2, p. 77–104, 2012.
Teles, JS, Fukuda, EY, Feder, D. Varfarina: perfil farmacológico e interações medicamentosas com antidepressivos Warfarin: pharmacological profile and drug interactions with antidepressants. Einstein, v. 10, n. 1, p. 110–115, 2012.
Mazzari, ALDA, Prieto, JM. Herbal medicines in Brazil: Pharmacokinetic profile and potential herb-drug interactions. Frontiers in Pharmacology, v. 5 JUL, n. July, p. 1–12, 2014.
Borrelli, F, Capasso, R, Izzo, AA. Garlic (Allium sativum L.): Adverse effects and drug interactions in humans. Molecular Nutrition and Food Research, v. 51, n. 11, p. 1386–1397, 2007.
Foster, BC, Foster, MS, Vandenhoek, S, et al. An In Vitro Evaluation of Human Cytochrome P450 3A4 and P-glycoprotein Inhibition by Garlic. Journal of Pharmacy & Pharmaceutical Sciences, v. 4, n. 2, p. 176–84, 2001.
Hiyasat, B, Sabha, D, Grötzinger, K. et al. Antiplatelet activity of Allium ursinum and Allium sativum. Pharmacology, v. 83, n. 4, p. 197–204, 2009.
Torres-Urrutia, C, Guzmán, L, Schmeda-Hirschmann, G, et al. Antiplatelet, anticoagulant, and fibrinolytic activity in vitro of extracts from selected fruits and vegetables. Blood Coagulation and Fibrinolysis, v. 22, n. 3, p. 197–205, 2011.
Markowitz, JS, Devane, CL, Chavin, KD, Taylor, RM, Ruan, Y, Donovan, JL. Effect of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther, 2003;74:170–7.
Amagase, H. Clarifying the Real Bioactive Constituents of Garlic. The Journal of Nutrition, v. 136, n. 3, p. 716S–725S, 2006.
Iciek, M, Kwiecień, I, Włodek, L. Biological properties of garlic and garlic-derived organosulfur compounds. Environmental and Molecular Mutagenesis, v. 50, n. 3, p. 247–265, 2009.
Wojcikowski, K, Myers, S, Brooks, L. Effects of garlic oil on platelet aggregation: A double blind placebo-controlled crossover study. Platelets, v. 18, n. 1, p. 29–34, 2007.
Leite, PM, Martins, MAP, Castilho, RO. Review on mechanisms and interactions in concomitant use of herbs and warfarin therapy. Biomedicine and Pharmacotherapy, v. 83, p. 14–21, 2016.
Mousa, SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods in Molecular Biology, v. 663, p. 229–240, 2010.
Allison, GL, Lowe, GM, Rahman, K. Aged garlic extract inhibits platelet activation by increasing intracellular cAMP and reducing the interaction of GPIIb/IIIa receptor with fibrinogen. Life Sciences, v. 91, n. 25–26, p. 1275–1280, 2012.
Steiner, M, Li, W. Aged Garlic Extract, a Modulator of Cardiovascular Risk Factors: A Dose-Finding Study on the Effects of AGE on Platelet Functions. The Journal of Nutrition, v. 131, n. 3, p. 980S–984S, 2001.
Greenblatt, DJ, Leigh-Pemberton, RA, Moltke, LL. In Vitro Interactions of Water-Soluble Garlic Components with Human Cytochromes P450. The Journal of Nutrition. v. 136, no. 3, p. 806S-809S, 2006.
Cavagnaro, PF, Camargo, A, Galmarini, CR, Simon, PW. Effect of cooking on garlic (Allium sativum L.) antiplatelet activity and thiosulfinates content. Journal of Agricultural and Food Chemistry, v. 55, n. 4, p. 1280–1288, 2007.
Ge, B, Zhang, Z, Zuo, Z. Updates on the clinical evidenced herb-warfarin interactions. Evidence-based Complementary and Alternative Medicine, v. 2014, 2014.
Bibi, Z. Role of cytochrome P450 in drug interactions. Nutrition and Metabolism, v. 5, n. 1, p. 27, 2008.
Panneerselvam, S, Yesudhas, D, Durai, P, Anwar, MA, Gosu, V, Choi, S. A combined molecular docking/dynamics approach to probe the binding mode of cancer drugs with cytochrome P450 3A4. Molecules, v. 20, n. 8, p. 14915–14935, 2015.
Lonsdale, R, Rouse, SL, Sansom, MSP, Mulholland, AJ. A Multiscale Approach to Modelling Drug Metabolism by Membrane-Bound Cytochrome P450 Enzymes. PLoS Computational Biology, v. 10, n. 7, 2014.
