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Stereoselective Formation and Metabolism of 20( S )‐Protopanaxadiol Ocotillol Type Epimers in Vivo and in Vitro
Author(s) -
Wang Wenyan,
Wang Li,
Wu Xiangmeng,
Xu Lixiao,
Meng Qingguo,
Liu Wanhui
Publication year - 2015
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.22407
Subject(s) - epimer , chemistry , glucuronidation , microsome , protopanaxadiol , stereoselectivity , glucuronide , metabolism , stereochemistry , metabolite , hydroxylation , in vivo , biochemistry , ginsenoside , in vitro , enzyme , ginseng , biology , medicine , alternative medicine , microbiology and biotechnology , pathology , catalysis
(20 S ,24 S )‐epoxy‐dammarane‐3,12,25‐triol (24 S ‐epimer) and (20 S ,24 R )‐epoxy‐ dammarane‐3,12,25‐triol (24 R ‐epimer), a pair of ocotillol type epimers, were identified as the main metabolites of 20( S )‐protopanaxadiol (PPD). The aim of this study was to systematically investigate the formation and metabolism of this pair of epimers in vivo and in vitro and to elucidate the isoforms of cytochrome P450 enzymes responsible for the stereoselective metabolism of both epimers. The result showed that 24 S ‐epimer was a more predominant ingredient in rat plasma after oral administration of PPD with higher area under the curve (AUC) values. Both the enzyme kinetic evaluations of the formation and elimination of 24 S ‐epimer and 24 R ‐epimer in rat liver microsomes (RLM) and human liver microsomes (HLM) indicated that 24 S ‐epimer had a higher formation rate and a lower oxygenation metabolism rate than 24 R ‐epimer, and the stereoselective differences were more obvious in HLM than in RLM. The chemical inhibition and recombinant human P450 isoforms assay showed that CYP3A4 was the predominant isoform responsible for the further metabolism of 24 R ‐epimer in HLM. The biliary excretion ratio of the 24 S ‐epimer glucuronide was more than 28‐fold higher than that of 24 R ‐epimer glucuronide after intravenous administration to rats, which also indicated 24 S ‐epimer was more preferential to be metabolized as the glucuronide conjugate than 24 R ‐epimer. Chirality 27:170–176, 2015 . © 2014 Wiley Periodicals, Inc.