[국내논문]Effects of gut microbiota on the pharmacokinetics of protopanaxadiol ginsenosides Rd, Rg3, F2, and compound K in healthy volunteers treated orally with red ginseng원문보기논문타임라인
Kim, Jeon-Kyung
(Neurobiota Research Center and Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
,
Choi, Min Sun
(Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University)
,
Jeung, Woonhee
(R&BD Center, Korea Yakult Co. Ltd.)
,
Ra, Jehyeon
(R&BD Center, Korea Yakult Co. Ltd.)
,
Yoo, Hye Hyun
(Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University)
,
Kim, Dong-Hyun
(Neurobiota Research Center and Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
Background: It is well recognized that gut microbiota is involved in the biotransformation of ginsenosides by converting the polar ginsenosides to nonpolar bioactive ginsenosides. However, the roles of the gut microbiota on the pharmacokinetics of ginsenosides in humans have not yet been fully eluci...
Background: It is well recognized that gut microbiota is involved in the biotransformation of ginsenosides by converting the polar ginsenosides to nonpolar bioactive ginsenosides. However, the roles of the gut microbiota on the pharmacokinetics of ginsenosides in humans have not yet been fully elucidated. Methods: Red ginseng (RG) or fermented red ginseng was orally administered to 34 healthy Korean volunteers, and the serum concentrations of the ginsenosides were determined using liquid chromatography-tandem mass spectrometry. In addition, the fecal ginsenoside Rd- and compound K (CK)eforming activities were measured. Then, the correlations between the pharmacokinetic profiles of the ginsenosides and the fecal ginsenoside-metabolizing activities were investigated. Results: For the RG group, the area under the serum concentratione-time curve values of ginsenosides Rd, F2, Rg3, and CK were 8.20 ± 11.95 ng·h/mL, 4.54 ± 3.70 ng·h/mL, 36.40 ± 19.68 ng·h/mL, and 40.30 ± 29.83 ng·h/mL, respectively. For the fermented red ginseng group, the the area under curve from zero to infinity (AUC∞) values of ginsenosides Rd, F2, Rg3, and CK were 187.90 ± 95.87 ng·h/mL, 30.24 ± 41.87 ng·h/mL, 28.68 ± 14.27 ng·h/mL, and 137.01 ± 96.16 ng·h/mL, respectively. The fecal CK-forming activities of the healthy volunteers were generally proportional to their ginsenoside Rd-eforming activities. The area under the serum concentration-time curve value of CK exhibited an obvious positive correlation (r = 0.566, p < 0.01) with the fecal CK-forming activity. Conclusion: The gut microbiota may play an important role in the bioavailability of the nonpolar RG ginsenosides by affecting the biotransformation of the ginsenosides.
Background: It is well recognized that gut microbiota is involved in the biotransformation of ginsenosides by converting the polar ginsenosides to nonpolar bioactive ginsenosides. However, the roles of the gut microbiota on the pharmacokinetics of ginsenosides in humans have not yet been fully elucidated. Methods: Red ginseng (RG) or fermented red ginseng was orally administered to 34 healthy Korean volunteers, and the serum concentrations of the ginsenosides were determined using liquid chromatography-tandem mass spectrometry. In addition, the fecal ginsenoside Rd- and compound K (CK)eforming activities were measured. Then, the correlations between the pharmacokinetic profiles of the ginsenosides and the fecal ginsenoside-metabolizing activities were investigated. Results: For the RG group, the area under the serum concentratione-time curve values of ginsenosides Rd, F2, Rg3, and CK were 8.20 ± 11.95 ng·h/mL, 4.54 ± 3.70 ng·h/mL, 36.40 ± 19.68 ng·h/mL, and 40.30 ± 29.83 ng·h/mL, respectively. For the fermented red ginseng group, the the area under curve from zero to infinity (AUC∞) values of ginsenosides Rd, F2, Rg3, and CK were 187.90 ± 95.87 ng·h/mL, 30.24 ± 41.87 ng·h/mL, 28.68 ± 14.27 ng·h/mL, and 137.01 ± 96.16 ng·h/mL, respectively. The fecal CK-forming activities of the healthy volunteers were generally proportional to their ginsenoside Rd-eforming activities. The area under the serum concentration-time curve value of CK exhibited an obvious positive correlation (r = 0.566, p < 0.01) with the fecal CK-forming activity. Conclusion: The gut microbiota may play an important role in the bioavailability of the nonpolar RG ginsenosides by affecting the biotransformation of the ginsenosides.
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가설 설정
In this study, we investigated the pharmacokinetic properties of the protopanaxadiol ginsenosides, including Rd, Rg3, F2, and CK, in humans after the intake of conventional RG and fermented red ginseng (FRG). Then, we analyzed the relationships between the pharmacokinetic profiles of the ginsenoside metabolites and ginsenoside metabolizing activity of human fecal microbiota.
제안 방법
In this study, we investigated the pharmacokinetic properties of the protopanaxadiol ginsenosides, including Rd, Rg3, F2, and CK, in humans after the intake of conventional RG and fermented red ginseng (FRG). Then, we analyzed the relationships between the pharmacokinetic profiles of the ginsenoside metabolites and ginsenoside metabolizing activity of human fecal microbiota.
Any food or water intake was not allowed during the first 4 h after administration of ginseng extracts. Venous blood samples (10 mL) were collected before the administration and at 1, 3, 6, 9, 12, and 24 h after the administration of RG or FRG in dry nonheparinized centrifuge tubes. Serum was collected by centrifugation at 10,000 Χ g for 5 min.
Calibration curves were generated by plotting the peak area ratio of the analyte to the IS versus the concentration of the analyte, using least-square linear regression. The intraday and interday accuracy and precision of the assay were evaluated by repeated analyses of samples at LQ, MQ, and HQ for three consecutive days.
The Phoenix WinNonlin Enterprise program (version 5.3; Pharsight Inc., St. Louis, MO, USA) was used with a noncompartmental statistical model to determine the following pharmacokinetic parameters: Cmax (maximum serum concentration), Tmax (the time taken to reach maximum), AUCt (the area under curve from zero to the last time point), AUCN (the area under curve from zero to infinity), and t1/2 (elimination half-life).
In this study, we investigated the pharmacokinetic profiles of protopanaxadiol ginsenosides in humans after the administration of RG extracts (RG and FRG), and then, we analyzed their correlations with the fecal ginsenoside-metabolizing activities. The enzymes of the gut bacteria seemed to exert their metabolic activity mainly on the biotransformation into ginsenoside CK via ginsenoside Rd rather than ginsenoside Rg3.
대상 데이터
Physically healthy men and women, aged between 20 and 45 years, were recruited from H Plus Yangji Hospital (Seoul, Korea). Participants were recruited if antibacterial, antidiarrhea, and laxative medications were not given within 1 month before the study.
The volunteers were admitted to the hospital 2 days after the final administration and were randomly assigned to receive RG or FRG. The RG group consisted of 13 men and 4 women, and the FRG group consisted of 13 men and 5 women. All volunteers were given standardized meals, and no food intake was permitted after 20:00 pm.
데이터처리
Calibration curves were generated by plotting the peak area ratio of the analyte to the IS versus the concentration of the analyte, using least-square linear regression. The intraday and interday accuracy and precision of the assay were evaluated by repeated analyses of samples at LQ, MQ, and HQ for three consecutive days.
All pharmacokinetic (PK) data were summarized as mean standard deviation. A one-way analysis of variance followed by the Student t-test was conducted to compare the means of different groups using SPSS (version 24; IBM Corporation, Armonk, NY, USA). Spearman’s rank correlation analysis was conducted using SPSS to determine the correlation coefficient between the area under the serum concentration-time curve (AUC) of ginsenosides and fecal bacterial ginsenoside-forming activity.
Spearman’s rank correlation analysis was conducted using SPSS to determine the correlation coefficient between the area under the serum concentration-time curve (AUC) of ginsenosides and fecal bacterial ginsenoside-forming activity.
성능/효과
4. The mean Tmax value of Rg3 was 5.69 3.38 h, and the mean Tmax values of Rd, F2, and CK were 9.41 4.42 h,9.32 3.38 h, and 10.35 4.06 h, respectively.
1, ginsenoside Rg3 is known to be generated by heat processing, such as steaming, rather than microbial biotransformation. The data from the FRG group revealed that ginsenoside Rg3 was not likely generated from ginsenoside Rd or the other polar ginsenosides via the gut microbiota enzymes. The Tmax profiles of Rg3 also support this.
However, when data set was confined to the FRG group, the correlation between the fecal Rd-forming activity and the AUC values of ginsenosides Rd, F2, and CK was statistically significant (r = 0.451, p < 0.05) (Fig. 5C).
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