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.

Xiangrong Zhang,Li Liu,Zhenghong Guo,Yuqing Zhao,Wei Li,Baoshan Sun,Ji Zhang,Caihong Shi,Junxuan Lu

doi:10.1371/journal.pone.0094962

Xiangrong Zhang, Li Liu + Show 7 more

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https://doi.org/10.1371/journal.pone.0094962

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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.

Highlights

Panax ginseng, a traditional herbal medicine used in the Eastern Asia for more than 2000 years, is presently being used worldwide as one of the most common complementary alternative medicines [1]
The root of Panax ginseng, has various health benefits, ranging from overcoming fatigue to treating severe cardiac and cancer problems [2,3,4,5]. 25-methoxydammarane-3, 12, 20-triol (25-OCH3-PPD) was a novel dammarane-type triterpene sapogenin that was first reported by Zhao [6,7], from the leaves of P.notoginseng. 25-OCH3-PPD exerts the strongest activity among any of the known ginsenosides tested for cytotoxic effects [8]
We found that 25(S)-OCH3-PPD could be absorbed with an absolute bioavailability of 19.7% 67.6% (10 mg/kg) in rats [12]. 25-OCH3-PPD was converted to 25-OH-PPD in rats after oral gavage or iv injection. 25(S)-OCH3PPD was metabolized to form active 25-OH-PPD after oral and intravenous administration

Summary

Introduction

A traditional herbal medicine used in the Eastern Asia for more than 2000 years, is presently being used worldwide as one of the most common complementary alternative medicines [1]. 25-OCH3-PPD exerts the strongest activity among any of the known ginsenosides tested for cytotoxic effects [8]. It is an effective inhibitor of cell growth and proliferation and inducer of apoptosis and cell cycle arrest. 25-OCH3-PPD had significant, dose-dependent effects on apoptosis, proliferation, and cell cycle progression. 25(R)OCH3-PPD (Figure 1) showed anti-lung cancer activity by activation of p38 MAPK pathway and generation of reactive oxygen species [11]. 20(S) and 20(R) forms of 25-OCH3-PPD are stereoisomers of each other that depend on the orientation of the C-20 hydroxyl. We found that 25(S)-OCH3-PPD could be absorbed with an absolute bioavailability of 19.7% 67.6% (10 mg/kg) in rats [12].

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