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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
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil
,
Fernanda de Lima Moreira
2   Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil
,
Norberto Peporine Lopes
3   Núcleo 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
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil
› Author Affiliations
Further Information

Publication History

received 21 September 2016
revised 25 November 2016

accepted 19 December 2016

Publication Date:
10 January 2017 (online)

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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 Ki 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 KI, kinact, and kinact/KI 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 kinact/KI 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

Supporting Information

Sample preparation conditions using liquid-liquid extraction, analysis conditions and HPLC- DAD chromatograms for the analysis of CYP450 metabolites and internal standards, evaluation of GRA solubility in sodium phosphate buffer, effect of Cremophor EL on CYP1A2 activity, IC50 determinations for well-known selective inhibitors of CYP450 enzymes, and time- and NADPH-dependent inhibition of CYP2C9 by GRA are available as Supporting Information.

 

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