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DOI: 10.1055/a-2078-5920
Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F
This 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.

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.
Supporting Information
- 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.
Publication History
Received: 12 February 2023
Accepted after revision: 21 April 2023
Accepted Manuscript online:
21 April 2023
Article published online:
26 May 2023
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