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Planta Med 2023; 89(11): 1097-1105
DOI: 10.1055/a-2078-5920
Natural Product Chemistry and Analytical Studies
Original Papers

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Fernando Bombarda Oda 
1   Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil
,
Flávio Alexandre Carvalho 
1   Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil
,
Priscila Akemi Yamamoto
2   Center of Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
3   School of Pharmaceutical Sciences of Ribeirão Preto, University of São Palo (USP), Ribeirão Preto, SP, Brazil
,
Jonata Augusto de Oliveira
1   Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil
,
Rosângela Gonçalves Peccinini
1   Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil
,
Guilherme Julião Zocolo
4   Embrapa Agroindústria Tropical, Empresa Brasileira de Pesquisa Agropecuária (Embrapa), Fortaleza, CE, Brazil
,
Paulo Riceli Vasconcelos Ribeiro
4   Embrapa Agroindústria Tropical, Empresa Brasileira de Pesquisa Agropecuária (Embrapa), Fortaleza, CE, Brazil
,
Natália Valadares de Moraes 
2   Center of Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
,
André Gonzaga dos Santos
1   Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil
› Author AffiliationsThis study was financed, in part, by the National Institute of Science and Technology on Biodiversity and Natural Products – INCT-BioNat (CNPq), Sao Paulo Research Foundation (FAPESP – Grants #465637/2014-0 and 2014/50265-3) and the Coordination for the Improvement of Higher Education – Brazil (CAPES) – Finance Code 001.
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Abstract

Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory, and antiulcerogenic medicines. The clerodane diterpenes casearin B and caseargrewiin F are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of casearin B and caseargrewiin F were not previously investigated. We aimed to assess the stability of casearin B and caseargrewiin F in physiological conditions and their metabolism in human liver microsomes. The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of casearin B and caseargrewiin F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism was not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed a octanol/water partition coefficient in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 and 66.4 µM and Vmax values of 327 and 648 nmol/min/mg of protein for casearin B and caseargrewiin F, respectively. Metabolism parameters in human liver microsomes were extrapolated to predict human hepatic clearance, and suggest that caseargrewiin F and casearin B have a high hepatic extraction ratio. In conclusion, our data suggest that caseargrewiin F and casearin B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.

Key words

Casearia sylvestris - Salicaceae - clerodane diterpene - hepatic metabolism - IVIVE

Supporting Information

    Additional information on the analytical and bioanalytical method validation, fu,p and fu,mic values, log P calibration curve, casg F and cas B stability in HLM, and 1H- and 13C-NMR data of casg F and cas B are available as Supporting Information.

  • Supporting Information


Publication History

Received: 12 February 2023

Accepted after revision: 21 April 2023

Accepted Manuscript online:
21 April 2023

Article published online:
26 May 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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