Document Detail

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates.
MedLine Citation:
PMID:  22943175     Owner:  NLM     Status:  In-Data-Review    
Objectives  Glycyrrhetinic acid is the main metabolite of glycyrrhizin and the main active component of Licorice root. This study was designed to investigate the in-vitro metabolism of glycyrrhetinic acid by liver microsomes and to examine possible metabolic interactions that glycyrrhetinic acid may have with other cytochrome P450 (CYP) substrates. Methods  Glycyrrhetinic acid was incubated with rat liver microsomes (RLM) and human liver microsomes (HLM). Liquid chromatography tandem mass spectrometry was used for glycyrrhetinic acid or substrates identification and quantification. Key findings  The K(m) and V(max) values for HLM are 33.41 µm and 2.23 nmol/mg protein/min, respectively; for RLM the K(m) and V(max) were 24.24 µm and 6.86 nmol/mg protein/min, respectively. CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. Other human CYP isoforms have minimal or no activity toward glycyrrhetinic acid. The interactions of glycyrrhetinic acid and six CYP substrates, such as phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, chlorzoxazone and midazolam were also investigated. The inhibitory action of glycyrrhetinic acid was observed in CYP2C9 for 4-hydroxylation of diclofenac, CYP2C19 for 4'-hydroxylation of (S)-mephenytoin and CYP3A4 for 1'-hydroxylation of midazolam with half maximal inhibitory concentration (IC50) values of 4.3-fold, 3.8-fold and 9.6-fold higher than specific inhibitors in HLM, respectively. However, glycyrrhetinic acid showed relatively little inhibitory effect (IC50 > 400 µm) on phenacetin O-deethylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation. Conclusions  The study indicated that CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. The results suggest that glycyrrhetinic acid has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP2C9, CYP2C19 and CYP3A4 substrates.
Kai Zhao; Ming Ding; Hui Cao; Zheng-Xin Cao
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Publication Detail:
Type:  Journal Article     Date:  2012-05-02
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  64     ISSN:  2042-7158     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-04     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1445-51     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.
Jiangsu Province Jintan People's Hospital Clinical Laboratory, Jintan Affiliated Hospital of Jiangsu University Clinical Laboratory, Zhenjiang, China.
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