Identification of 20(S)-Protopanaxadiol Metabolites in Human Liver Microsomes and Human Hepatocytes

Li, Liang; Chen, Xiaoyan; Li, Dan; Zhong, Dafang

doi:10.1124/dmd.110.036723

Cited by 78 publications

(76 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rg 5 , the principal component in steamed American ginseng, was also transformed to Rh 3 by human intestinal microflora [23]. Additionally, systematic metabolic behaviors of aglycon were further investigated and epoxidation metabolite was identified as the main metabolic pathway of protopanaxadiol [24,25], NPD [26], and protopanaxatriol [27] in rats. Accordingly, to investigate the detailed reason for low oral bioavailability, the metabolic routes of ocotillol type ginsenosides need to be explored in the near future.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Characterizations of Ginsenoside Ocotillol, RT5 and F11, the Promising Agents for Alzheimer’s Disease from American Ginseng, in Rats and Beagle Dogs

et al. 2019

Pharmacology

View full text Add to dashboard Cite

Background: Ocotillol, RT₅ and F₁₁, the main active components of ocotillol type ginsenosides, have attracted a lot of attention due to their beneficial effects on neurodegenerative disease models of Alzheimer’s disease. Pharmacokinetic (PK) is a bridge linking the herbal medicines and their pharmacological responses. However, few data are available regarding PK behaviors of ocotillol type ginsenosides. Methods: The liquid chromatography-tandem mass spectrometry methods were developed and validated to calculate the concentrations of 3 ginsenosides in different biological matrices. Rat and beagle dog plasma samples were deproteinized with methanol and separated on Shim-pack GIST C₁₈ column. All of the analytes were detected in positive ion mode using multiple reaction monitoring. Results: The methods showed good linearity (r > 0.996) in the established concentration range. All validated data, such as specificity, intra- and inter-day precision, accuracy, extraction recovery, matrix effect, and stability were within required limits. The values of C_max and AUC_(0–t) indicated ocotillol type ginsenosides had low systemic exposure and poor absorption into blood. T_1/2 and MRT_(0–t) demonstrated the elimination process of ocotillol type ginsenosides might be slow. Double peaks were observed in the mean plasma concentration versus time profiles of ocotillol, RT₅, and F₁₁ after oral intake. Conclusions: This was the first PK investigation of the ocotillol type ginsenosides in rats and beagle dogs. The results we found here were helpful to our understanding of the absorption mechanism of ocotillol type ginsenosides and provided the scientific basis for further pre-clinical research.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Characterizations of Ginsenoside Ocotillol, RT5 and F11, the Promising Agents for Alzheimer’s Disease from American Ginseng, in Rats and Beagle Dogs

et al. 2019

Pharmacology

View full text Add to dashboard Cite

show abstract

“…Actually, the resource distribution of ocotillol type saponins in nature is fewer than other dammarane type saponins mainly due to the existence in a small part of Panax species, which limits their wide applications [10,11] . Therefore, there is an increasing interest in chemical synthesis [12][13][14][15] and biotransformation [16,17] from dammarane type saponins to obtain ocotillol type saponins.…”

Section: Introductionmentioning

confidence: 99%

Semisynthesis and cytotoxicity evaluation of a series of ocotillol type saponins and aglycones from 20(S)-ginsenoside Rg2, Rh1, protopanaxatriol and their 20(R)-epimers

Yang

Cai

et al. 2016

Chem. Res. Chin. Univ.

View full text Add to dashboard Cite

With the oxidation treatment, eighteen compounds were separated from 20(S)-ginsenoside Rg 2 , Rh 1 , protopanaxatriol(PPT) and their 20(R)-epimers in total and cytotoxicity of most of them was evaluated against three human cancer cell lines HeLa, A549 and MCF-7 by 3-(4,5-dimetylthiazol-z-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Their structures were confirmed by means of nuclear magnetic resonance(NMR) and mass spectrometry and the results were compared with those of previous literature. In this study, we systematically semisynthesized all four ocotillol type saponins, i.e., (20S, 24S), (20S, 24R), (20R, 24S) and (20R, 24R). All the configurations at C20 kept the same with their starting materials. Meanwhile a pair of C24 epimers was generated in terms of ocotillol type saponins. In addition, seven compounds (4-8, 13 and 14) were reported firstly. The cytotoxic results distinguished the ocotillol type products (6, 7, 13 and 14) from 20(R)-PPT and 20(R)-ginsenoside Rh 1 , which possessed better cytotoxicities than their correspondents from 20(S)-epimers against HeLa cells, and the carbonyl group at C3 can improve the cytotoxicity, which helped us to gain deeper insight into Ocotillol type saponins.

show abstract

“…at ASPET Journals on May 10, 2018 dmd.aspetjournals.org vivo for years (Hasegawa et al, 1996;Tawab et al, 2003;Yang et al, 2006) and the human P450-mediated oxidation of the sapogenins has also been assessed in vitro recently (Kasai et al, 2000;Hao et al, 2010;Li et al, 2011). Unlike the situation in humans, these metabolites were poorly detected in rat plasma after PO dose of Sanqi-extract (Liu et al, 2009).…”

Section: Pharmacokinetics and Metabolism Of Ginsenosides In Humans 1465mentioning

confidence: 97%

Combinatorial Metabolism Notably Affects Human Systemic Exposure to Ginsenosides from Orally Administered Extract of Panax notoginseng Roots (Sanqi)

Yang

Cheng

et al. 2013

Drug Metab Dispos

View full text Add to dashboard Cite

Ginsenosides are medicinal ingredients of the cardiovascular herb Panax notoginseng roots (Sanqi). Here, we implemented a human study (ChiCTR-ONC-09000603; www.chictr.org) to characterize pharmacokinetics and metabolism of ginsenosides from an orally ingested Sanqi-extract (a 1:10 water extract of Sanqi) and the human plasma and urine samples were analyzed by liquid chromatographymass spectrometry. Plasma and urinary compounds derived from ginsenosides included: 1) intestinally absorbed ginsenosides Ra 3 , Rb 1 , Rd, F 2 , Rg 1 , and notoginsenoside R 1 ; and 2) the deglycosylated products compound-K, 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, and their oxidized metabolites. The systemic exposure levels of the first group compounds increased as the Sanqi-extract dose increased, but those of the second group compounds were doseindependent. The oxidized metabolites of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol represented the major circulating forms of ginsenosides in the bloodstream, despite their large interindividual differences in exposure level. The metabolites were formed via combinatorial metabolism that consisted of a rate-limiting step of ginsenoside deglycosylation by the colonic microflora and a subsequent step of sapogenin oxidation by the enterohepatic cytochrome P450 enzymes. Significant accumulation of plasma ginsenosides and metabolites occurred in the human subjects receiving 3-week subchronic treatment with the Sanqi-extract. Plasma 20(S)-protopanaxadiol and 20(S)-protopanaxatriol could be used as pharmacokinetic markers to reflect the subjects' microbial activities, as well as the timelychanges and interindividual differences in plasma levels of their respective oxidized metabolites. The information gained from the current study is relevant to pharmacology and therapeutics of Sanqi.

show abstract

Identification of 20(S)-Protopanaxadiol Metabolites in Human Liver Microsomes and Human Hepatocytes

Cited by 78 publications

References 22 publications

Pharmacokinetic Characterizations of Ginsenoside Ocotillol, RT<sub>5</sub> and F<sub>11</sub>, the Promising Agents for Alzheimer’s Disease from American Ginseng, in Rats and Beagle Dogs

Pharmacokinetic Characterizations of Ginsenoside Ocotillol, RT<sub>5</sub> and F<sub>11</sub>, the Promising Agents for Alzheimer’s Disease from American Ginseng, in Rats and Beagle Dogs

Semisynthesis and cytotoxicity evaluation of a series of ocotillol type saponins and aglycones from 20(S)-ginsenoside Rg2, Rh1, protopanaxatriol and their 20(R)-epimers

Combinatorial Metabolism Notably Affects Human Systemic Exposure to Ginsenosides from Orally Administered Extract of Panax notoginseng Roots (Sanqi)

Contact Info

Product

Resources

About