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

Fernando Bombarda Oda; Flávio Alexandre Carvalho; Priscila Akemi Yamamoto; Jonata Augusto de Oliveira; Rosângela Gonçalves Peccinini; Guilherme Julião Zocolo; Paulo Riceli Vasconcelos Ribeiro; Natália Valadares de Moraes; André Gonzaga dos Santos

doi:10.1055/a-2078-5920

Planta Medica, Table of Contents

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

¹Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil

,

Flávio Alexandre Carvalho

¹Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil

,

Priscila Akemi Yamamoto

²Center of Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA

³School of Pharmaceutical Sciences of Ribeirão Preto, University of São Palo (USP), Ribeirão Preto, SP, Brazil

,

Jonata Augusto de Oliveira

¹Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil

,

Rosângela Gonçalves Peccinini

¹Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil

,

Guilherme Julião Zocolo

⁴Embrapa Agroindústria Tropical, Empresa Brasileira de Pesquisa Agropecuária (Embrapa), Fortaleza, CE, Brazil

,

Paulo Riceli Vasconcelos Ribeiro

⁴Embrapa Agroindústria Tropical, Empresa Brasileira de Pesquisa Agropecuária (Embrapa), Fortaleza, CE, Brazil

,

Natália Valadares de Moraes

²Center of Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA

,

André Gonzaga dos Santos

¹Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (Unesp), Araraquara, SP, Brazil

› Author Affiliations

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 K_M values of 61.4 and 66.4 µM and V_max 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

Full Text

References

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