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Planta Med 2017; 83(08): 737-745
DOI: 10.1055/s-0042-124359
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro Metabolism of Artepillin C by Rat and Human Liver Microsomes

Daniel Blascke Carrão
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Nayara Cristina Perez de Albuquerque
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Lucas Maciel Mauriz Marques
2   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Antônio Eduardo Miller Crotti
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Alan Cesar Pilon
3   Nucleus of Bioassays, Biosynthesis and Ecophysiology of Natural Products – NuBBE, Sao Paulo State University – UNESP – Chemistry Institute, Department of Organic Chemistry, Araraquara, Sao Paulo, Brazil
,
Vanderlan Da Silva Bolzani
3   Nucleus of Bioassays, Biosynthesis and Ecophysiology of Natural Products – NuBBE, Sao Paulo State University – UNESP – Chemistry Institute, Department of Organic Chemistry, Araraquara, Sao Paulo, Brazil
,
Andresa Aparecida Berretta
4   Apis Flora Industrial e Comercial Ltda, Ribeirão Preto, SP, Brazil
,
Anderson Rodrigo Moraes de Oliveira
1   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
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Weitere Informationen

Publikationsverlauf

received 28. Juli 2016
revised 12. Dezember 2016

accepted 14. Dezember 2016

Publikationsdatum:
10. Januar 2017 (online)

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Abstract

Artepillin C, a natural product present in the Brazilian green propolis, has several biological properties. Among these properties, the antitumor action of this product is noteworthy and makes it a promising drug candidate for the treatment of several types of cancer. This paper describes the in vitro metabolism of Artepillin C in rat and human liver microsomes. The rat model suggested a sigmoidal profile for the metabolism, adapted to the Hillʼs kinetic model. The enzymatic kinetic parameters were as follows: maximal velocity = 0.757 ± 0.021 µmol/mg protein/min, Hill coefficient = 10.90 ± 2.80, and substrate concentration at which half-maximal velocity of a Hill enzyme is achieved = 33.35 ± 0.55 µM. Based on these results, the calculated in vitro intrinsic clearance for Artepillin C was 16.63 ± 1.52 µL/min/mg protein. The in vitro metabolism assay conducted on the human model did not fit any enzymatic kinetic model. Two novel metabolites were formed in both mammal microsomal models and their chemical structures were elucidated for the first time. The main human cytochrome P450 isoforms involved in Artepillin C metabolism had been identified, and the results suggest a majority contribution of CYP2E1 and CYP2C9 in the formation of the two metabolites.

Key words

Artepillin C - enzymatic kinetics - liver microsomes - natural product - in vitro metabolism

Supporting Information

LC-ESI-IT-MS/MS Fragmentation pattern of Artepillin C metabolites, method validation data and NMR data for Artepillin C metabolites are available as Supporting Information.

 

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