In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin

Maísa Daniela Habenschus; Fernanda de Lima Moreira; Norberto Peporine Lopes; Anderson R. M. de Oliveira

doi:10.1055/s-0042-124615

Planta Medica, Inhaltsverzeichnis

Planta Med 2017; 83(08): 727-736
DOI: 10.1055/s-0042-124615

Pharmacokinetic Investigations

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin

Maísa Daniela Habenschus

¹Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil

,

Fernanda de Lima Moreira

²Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil

,

Norberto Peporine Lopes

³Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil

,

Anderson R. M. de Oliveira

¹Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil

› Institutsangaben

Abstract

Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent K_i value for CYP2C9 was 50.60 µM and those for CYP3A4/5 were 48.71 µM and 31.25 µM using two different probe substrates, nifedipine and midazolam, respectively. The apparent K_I, k_inact, and k_inact/K_I ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 µM, 0.037 min⁻¹, and 5.78 mL · min⁻¹ µmol⁻¹, respectively, by examining nifedipine oxidation, and 31.53 µM, 0.049 min⁻¹, and 1.55 mL · min⁻¹ µmol⁻¹, respectively, by examining midazolam 1′-hydroxylation. These apparent k_inact/K_I values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC₅₀ > 200 µM and 100 µM, respectively). In contrast, from a concentration of 4 µM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin-drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked.

Key words

cytochrome p450 inhibition - grandisin - drug interactions - human liver microsomes - mechanism-based inhibition

Volltext

Referenzen

References
1 Lopes NP, Kato MJ, Yoshida M. Antifungal constituents from roots of Virola surinamensis . Phytochemistry 1999; 51: 29-33
2 Morais SKR, Teixeira AF, Torres ZES, Nunomura SM, Yamashiro-Kanashiro EH, Lindoso JAL, Yoshida M. Biological activities of lignoids from Amazon Myristicaceae species: Virola michelii, V. mollissima, V. pavonis and Iryanthera juruensis . J Braz Chem Soc 2009; 20: 1110-1118
3 Pu JX, Gao XM, Lei C, Xiao WL, Wang RR, Yang LB, Zhao Y, Li LM, Huang SX, Zheng YT, Sun HD. Three new compounds from Kadsura longipedunculata . Chem Pharm Bull 2008; 56: 1143-1146
4 Saad JM, Soepadamo E, Fang XP, McLaughlin JL, Fanwick PE. (−)-Grandisin from Cryptocarya crassinervia . J Nat Prod 1991; 54: 1681-1683
5 Carvalho AA, Galdino PM, Nascimento MV, Kato MJ, Valadares MC, Cunha LC, Costa EA. Antinociceptive and antiinflammatory activities of grandisin extracted from Virola surinamensis . Phytother Res 2010; 24: 113-118
6 Ramos CS, Vanin SA, Kato MJ. Metabolism of (−)-grandisin from Piper solmsianum in Coleoptera and Lepidoptera species. Phytochemistry 2008; 69: 2157-2161
7 Cabral MM, Alencar JA, Guimarães AE, Kato MJ. Larvicidal activity of grandisin against Aedes Aegypti . J Am Mosq Control Assoc 2009; 25: 103-105
8 Leite ACCF, Kato MJ, Soares ROA, Guimarães AE, Santos-Mallet JR, Cabral MMO. Grandisin caused morphological changes larval and toxicity on Aedes aegypti . Braz J Pharm 2012; 22: 517-521
9 Zhang HJ, Tamez PA, Hoang VD, Tan GT, Hung NV, Xuan LT, Huong LM, Cuong NM, Thao DT, Soejarto DD, Fong HHS, Pezzuto JM. Antimalarial compounds from Rhaphidophora decursiva . J Nat Prod 2001; 64: 772-777
10 Lopes NP, Chicaro P, Kato MJ, Albuquerque S, Yoshida M. Flavonoids and lignans from Virola surinamensis twigs and their in vitro activity against Trypanosoma cruzi . Planta Med 1998; 64: 667-669
11 Bernardes LS, Kato MJ, Albuquerque S, Carvalho I. Synthesis and trypanocidal activity of 1,4-bis-(3,4,5-trimethoxy-phenyl)-1,4-butanediol and 1,4-bis-(3,4-dimethoxyphenyl)-1,4-butanediol. Bioorg Med Chem 2006; 14: 7075-7082
12 Martins RCC, Latorre LR, Sartorelli P, Kato MJ. Phenylpropanoids and tetrahydrofuran lignans from Piper solmsianum . Phytochemistry 2000; 55: 843-846
13 Verza M, Arakawa NS, Lopes NP, Kato MJ, Pupo MT, Said S, Carvalho I. Biotransformation of a tetrahydrofuran lignan by the endophytic fungus Phomopsis Sp . J Braz Chem Soc 2009; 20: 195-200
14 De Santis Ferreira L, Callejon DR, Engemann A, Cramer B, Humpf HU, de Barros VP, Assis MD, da Silva DB, de Albuquerque S, Okano LT, Kato MJ, Lopes NP. In vitro metabolism of grandisin, a lignan with anti-chagasic activity. Planta Med 2012; 78: 1939-1941
15 Valadares MC, de Oliveira Jr. LM, de Carvalho FS, Andrade LV, dos Santos AP, de Oliveira V, Gil Ede S, Kato MJ. Chemoprotective effect of the tetrahydrofuran lignan grandisin in the in vivo rodent micronucleus assay. J Pharm Pharmacol 2011; 63: 447-451
16 Valadares MC, de Carvalho IC, de Oliveira Jr. L, Vieira Mde S, Benfica PL, de Carvalho FS, Andrade LV, Lima EM, Kato MJ. Cytotoxicity and antiangiogenic activity of grandisin. J Pharm Pharmacol 2009; 61: 1709-1714
17 Oga EF, Sekine S, Shitara Y, Horie T. Pharmacokinetic herb-drug interactions: Insight into mechanisms and consequences. Eur J Drug Metab Pharmacokinet 2016; 41: 93-108
18 Taesotikul T, Dumrongsakulchai W, Wattanachai N, Navinpipat V, Somanabandhu A, Tassaneeyakul W, Tassaneeyakul W. Inhibitory effects of Phyllanthus amarus and its major lignans on human microsomal cytochrome P450 activities: evidence for CYP3A4 mechanism-based inhibition. Drug Metab Pharmacokinet 2011; 26: 154-161
19 Ring B, Wrighton SA, Mohutsky M. Reversible Mechanisms of Enzyme Inhibition and resulting clinical Significance. In: Nagar S, Argikar UA, Tweedie DJ. eds. Enzyme Kinetics in Drug Metabolism – Fundamentals and Applications. New York: Human Press; 2014: 37-56
20 Njuguna NM, Masimirembwa C, Chibale K. Identification and characterization of reactive metabolites in natural products-driven drug discovery. J Nat Prod 2012; 75: 507-513
21 Food and Drug Administration (FDA). FDA guidance for industry drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendation. Available at. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf Accessed November 11, 2016
22 Sun M, Tang Y, Ding T, Liu M, Wang X. Investigation of cytochrome P450 inhibitory properties of maslinic acid, a bioactive compound from Olea europaea L., and its structure-activity relationship. Phytomedicine 2015; 22: 56-65
23 Barth T, Habenschus MD, Lima Moreira F, Ferreira Lde S, Lopes NP, de Oliveira ARM. In vitro metabolism of the lignan (−)-grandisin, an anticancer drug candidate, by human liver microsomes. Drug Test Anal 2015; 7: 780-786
24 Hartman JH, Boysen G, Miller GP. Cooperative effects for CYP2E1 differ between styrene and its metabolites. Xenobiotica 2013; 43: 755-764
25 Dey A. Cytochrome P450 2E1: its clinical Aspects and a brief Perspective on the current Research Scenario. In: Dey A. ed. Cytochrome P450 2E1: its Role in Disease and Drug Metabolism. New York: Springer; 2013
26 Gonzalez FJ. Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 2005; 569: 101-110
27 Lu Y, Cederbaum AI. Cisplatin-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 2E1. Toxicol Sci 2005; 89: 515-525
28 Testino SA, Patonay G. High-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2003; 30: 1459-1467
29 Sakaeda T, Iwaki K, Kakumoto M, Nishikawa M, Niwa T, Jin JS, Nakamura T, Nishiguchi K, Okamura N, Okamura K. Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs. J Pharm Pharmacol 2005; 57: 759-764
30 Dinger J, Meyer MR, Maurer HH. Development of an in vitro cytochrome P450 cocktail inhibition assay for assessing the inhibition risk of drugs of abuse. Toxicol Lett 2014; 230: 28-35
31 Mohotsky M, Hall SD. Irreversible Enzyme Inhibition Kinetics and Drug – Drug Interactions. In: Nagar S, Argikar UA, Tweedie DJ. eds. Enzyme Kinetics in Drug Metabolism. New York: Human Press; 2014: 57-92
32 Ogilvie BW, Usuki E, Yerino P, Parkison A. In vitro Approaches for studying the Inhibition of Drug-metabolizing Enzymes and identifying the Drug- metabolizing Enzymes responsible for the Metabolism of Drugs (Reaction phenotyping) with Emphasis on Cytochrome P450. In: Rodrigues AD. ed. Drug-Drug Interactions. 2nd ed. New York: Informa Healthcare; 2008
33 Clark SE, Jones BC. Human Cytochrome p450 and their Role in Metabolism-based Drug-Drug Interactions. In: Rodrigues AD. ed. Drug-Drug Interactions. 2nd ed. New York: Informa Healthcare; 2008
34 Qin CZ, Lv QL, Wu NY, Cheng L, Chu YC, Chu TY, Hu L, Cheng Y, Zhang X, Zhou HH. Mechanism-based inhibition of Alantolactone on human cytochrome P450 3A4 in vitro and activity of hepatic cytochrome P450 in mice. J Ethnopharmacol 2015; 168: 146-149
35 Mao J, Tay S, Khojasteh CS, Chen Y, Hop CEA, Kenny JR. Evaluation of time dependent inhibition assays for marketed oncology drugs: Comparison of human hepatocytes and liver microsomes in the presence and absence of human plasma. Pharm Res 2016; 33: 1204-1219
36 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: 3-13
37 Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KHJ, Lu C, Nomeir AA, Seibert E, Skordos KW, Tonn GR, Horn RV, Wang RW, Wong YN, Yang TJ, Obach RS. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 2009; 37: 1355-1370
38 Sun S, Liu G, Wang Y. Simultaneous determination of acetaminophen, caffeine, and chlorphenamine maleate in paracetamol and chlorphenamine maleate granules. Chromatographia 2006; 64: 719-724
39 Asfak V, Mrinalini D, Leena B, Rahul G. Simultaneous determination of diclofenac sodium and rabeprazole sodium in bulk and pharmaceutical dosage form by LC. Chromatographia 2007; 66: 941-943
40 Patki KC, von Moltke LL, Greeblatt DJ. In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes P450: role of CYP3A4 and CYP3A5. Drug Metab Dispos 2003; 31: 938-944
41 Saxena A, Jain GK, Siddigui HH, Bhunia SS, Saxena AK, Gayen JR. In vitro metabolism of a novel antithrombotic compound, S002–333, and its enantiomers: quantitative cytochrome P450 phenotyping, metabolic profiling and enzyme kinetic studies. Xenobiotica 2014; 44: 295-308
42 Zebothsen I, Kunze T, Clement B. Inhibitory effects of cytostatically active 6-aminobenzo[c]phenanthridines on cytochrome P450 enzymes in human hepatic microsomes. Basic Clin Pharmacol Toxicol 2006; 99: 37-43
43 Rastogi H, Jana S. Evaluation of inhibitory effects of caffeic acid and quercetin on human liver cytochrome P450 activities. Phytother Res 2014; 28: 1873-1878
44 Bae SH, Kwon MJ, Choi EJ, Zheng YF, Yoon KD, Liu KH, Bae SK. Potent inhibition of cytochrome P450 2B6 by sibutramine in human liver microsomes. Chem Biol Interact 2013; 205: 11-19
45 Nirogi R, Palacharla RC, Mohammed AR, Manoharan A, Ponnamaneni RK, Bhyrapuneni G. Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction. Chem Biol Interact 2015; 230: 9-20

Zusatzmaterial

Supporting Information