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. 2017 Mar 7:8:101.
doi: 10.3389/fphar.2017.00101. eCollection 2017.

Ganoderic Acid A Metabolites and Their Metabolic Kinetics

Fang-Rui Cao  1 , Li Feng  1 , Lin-Hu Ye  1 , Li-Sha Wang  1 , Bing-Xin Xiao  1 , Xue Tao  1 , Qi Chang  1
Affiliations

Ganoderic Acid A Metabolites and Their Metabolic Kinetics

Fang-Rui Cao et al. Front Pharmacol. .

Abstract

Ganoderic acid A (GAA), a representative active triterpenoid from Ganoderma lucidum, has been reported to exhibit antinociceptive, antioxidative, cytotoxic, hepatoprotective and anticancer activities. The present study aims (1) to identify GAA metabolites, in vivo by analyzing the bile, plasma and urine after intravenous administration to rats (20 mg/kg), and in vitro by incubating with rat liver microsomes (RLMs) and human liver microsomes (HLMs); (2) to investigate the metabolic kinetics of main GAA metabolites. Using HPLC-DAD-MS/MS techniques, a total of 37 metabolites were tentatively characterized from in vivo samples based on their fragmentation behaviors. The metabolites detected in in vitro samples were similar to those found in vivo. GAA underwent extensive phase I and II metabolism. The main metabolic soft spots of GAA were 3, 7, 11, 15, 23-carbonyl groups (or hydroxyl groups) and 12, 20, 28 (29)-carbon atoms. Ganoderic acid C2 (GAC2) and 7β,15-dihydroxy-3,11,23-trioxo-lanost-26-oic acid were two main reduction metabolites of GAA, and their kinetics followed classical hyperbolic kinetics. The specific isoenzyme responsible for the biotransformation of the two metabolites in RLMs and HLMs was CYP3A. This is the first report on the comprehensive metabolism of GAA, as well as the metabolic kinetics of its main metabolites.

Keywords: HPLC-DAD-MS/MS; UFLC-MS/MS; ganoderic acid A; metabolic kinetics; metabolites.

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Figures

Figure 1
Figure 1
Total ion chromatograms of rat bile samples before (A) and after intravenous administration of GAA at 20 mg/kg (B).
Figure 2
Figure 2
Extracted ion chromatograms of GAA metabolites in rat bile sample after intravenous administration of GAA at 20 mg/kg.
Figure 3
Figure 3
Extracted ion chromatograms of GAA hydroxylation metabolites in plasma and GAA oxidoreduction metabolites in urine. (A) Blank plasma; (B) plasma sample after intravenous administration of GAA at 20 mg/kg; (C) blank urine; (D) urine sample after intravenous administration of GAA at 20 mg/kg.
Figure 4
Figure 4
The mass spectrum and proposed fragmentation pathways of GAA.
Figure 5
Figure 5
Proposed metabolic pathways of GAA in rats and structures of its metabolites.
Figure 6
Figure 6
Formation kinetics of GAA metabolites M2 and M4 in pooled RLMs (A) or HLMs (B,C). (mean ± SD, n = 3).
Figure 7
Figure 7
Effect of CYP inhibitors on the formation of GAA metabolites M2 and M4 in pooled RLMs (A) or HLMs (B). GAA was incubated with pooled RLMs or HLMs with and without α-naphthoflavone (NAP), ticlopidine (TIC), quinidine (QND), ketoconazole (KET), fluconazole (FLU) and diethyldithiocarbamate (DIE). *p < 0.05, ***p < 0.001, compared vs. control. (mean ± SD, n = 3).
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