In vitro metabolism of 20(R)-25-methoxyl-dammarane-3, 12, 20-triol from Panax notoginseng in human, monkey, dog, rat, and mouse liver microsomes

PLoS One. 2014 Apr 15;9(4):e94962. doi: 10.1371/journal.pone.0094962. eCollection 2014.

Abstract

The present study characterized in vitro metabolites of 20(R)-25-methoxyl-dammarane-3β, 12β, 20-triol (20(R)-25-OCH3-PPD) in mouse, rat, dog, monkey and human liver microsomes. 20(R)-25-OCH3-PPD was incubated with liver microsomes in the presence of NADPH. The reaction mixtures and the metabolites were identified on the basis of their mass profiles using LC-Q/TOF and were quantified using triple quadrupole instrument by multiple reaction monitoring. A total of 7 metabolites (M1-M7) of the phase I metabolites were detected in all species. 25(R)-OCH3-PPD was metabolized by hydroxylation, dehydrogenation, and O-demethylation. Enzyme kinetic of 20(R)-25-OCH3-PPD metabolism was evaluated in rat and human hepatic microsomes. Incubations studies with selective chemical inhibitors demonstrated that the metabolism of 20(R)-25-OCH3-PPD was primarily mediated by CYP3A4. We conclude that 20(R)-25-OCH3-PPD was metabolized extensively in mammalian species of mouse, rat, dog, monkey, and human. CYP3A4-catalyzed oxygenation metabolism played an important role in the disposition of 25(R)-OCH3-PPD, especially at the C-20 hydroxyl group.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dammaranes
  • Dogs
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Male
  • Metabolic Networks and Pathways
  • Metabolomics* / methods
  • Mice
  • Microsomes, Liver / metabolism*
  • Panax notoginseng / chemistry*
  • Rats
  • Triterpenes / chemistry
  • Triterpenes / metabolism*

Substances

  • Triterpenes

Grants and funding

This work is mainly supported by National Science and Technology Major Project and “Key New Drug Creation and Manufacturing Program” (2009ZX09102-114), National Nature Science Foundation of China (Admission No. 81273389, 81302662, http://www.nsfc.gov.cn) and Liaoning Province Education Administration (No. L2012364). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.