[국내논문]Tolerability and pharmacokinetics of ginsenosides Rb1, Rb2, Rc, Rd, and compound K after single or multiple administration of red ginseng extract in human beings원문보기
Choi, Min-Koo
(College of Pharmacy, Dankook University)
,
Jin, Sojeong
(College of Pharmacy, Dankook University)
,
Jeon, Ji-Hyeon
(Research Institute of Pharmaceutical Sciences and College of Pharmacy, Kyungpook National University)
,
Kang, Woo Youl
(Clinical Trial Center, Kyungpook National University Hospital)
,
Seong, Sook Jin
(Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Graduate School, Kyungpook National University)
,
Yoon, Young-Ran
(Clinical Trial Center, Kyungpook National University Hospital)
,
Han, Yong-Hae
(Life Science Institute, Daewoong Pharmaceutical)
,
Song, Im-Sook
(Research Institute of Pharmaceutical Sciences and College of Pharmacy, Kyungpook National University)
Background: We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Methods: Red ginseng extract (dried ginseng > 60%) was administered once a...
Background: We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Methods: Red ginseng extract (dried ginseng > 60%) was administered once and repeatedly for 15 days to 15 healthy Korean people. After single and repeated administration of red ginsengextract, blood sample collection, measurement of blood pressure and body temperature, and routine laboratory test were conducted over 48-h test periods. Results: Repeated administration of high-dose red ginseng for 15 days was well tolerated and did not produce significant changes in body temperature or blood pressure. The plasma concentrations of Rb1, Rb2, and Rc were stable and showed similar area under the plasma concentration-time curve (AUC) values after 15 days of repeated administration. Their AUC values after repeated administration of red ginseng extract for 15 days accumulated 4.5- to 6.7-fold compared with single-dose AUC. However, the plasma concentrations of Rd and compound K showed large interindividual variations but correlated well between AUC of Rd and compound K. Compound K did not accumulate after 15 days of repeated administration of red ginseng extract. Conclusion: A good correlation between the AUC values of Rd and compound K might be the result of intestinal biotransformation of Rb1, Rb2, and Rc to Rd and subsequently to compound K, rather than the intestinal permeability of these ginsenosides. A strategy to increase biotransformation or reduce metabolic intersubject variability may increase the plasma concentrations of Rd and compound K.
Background: We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Methods: Red ginseng extract (dried ginseng > 60%) was administered once and repeatedly for 15 days to 15 healthy Korean people. After single and repeated administration of red ginsengextract, blood sample collection, measurement of blood pressure and body temperature, and routine laboratory test were conducted over 48-h test periods. Results: Repeated administration of high-dose red ginseng for 15 days was well tolerated and did not produce significant changes in body temperature or blood pressure. The plasma concentrations of Rb1, Rb2, and Rc were stable and showed similar area under the plasma concentration-time curve (AUC) values after 15 days of repeated administration. Their AUC values after repeated administration of red ginseng extract for 15 days accumulated 4.5- to 6.7-fold compared with single-dose AUC. However, the plasma concentrations of Rd and compound K showed large interindividual variations but correlated well between AUC of Rd and compound K. Compound K did not accumulate after 15 days of repeated administration of red ginseng extract. Conclusion: A good correlation between the AUC values of Rd and compound K might be the result of intestinal biotransformation of Rb1, Rb2, and Rc to Rd and subsequently to compound K, rather than the intestinal permeability of these ginsenosides. A strategy to increase biotransformation or reduce metabolic intersubject variability may increase the plasma concentrations of Rd and compound K.
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문제 정의
Therefore, the objective of this study was to examine the tolerability and pharmacokinetic properties of various ginsenosides such as Rb1, Rb2, Rc, Rd, and compound K after single or multiple administrations of red ginseng extract in human beings and to investigate the intestinal permeability of these ginsenosides in Caco-2 cell system.
제안 방법
Physical examination and routine laboratory tests (serum chemistry, urinalysis, and hematology) were performed at screening, before red ginseng administration on days 1 and 15 and at the follow-up visit (7 ± 2 days after the last dose).
Healthy individuals who participated in this study were aged ≥ 19 years and with body weight ≥ 50 kg. They had no clinically significant abnormalities as confirmed by the clinical laboratory test, detailed physical examination, serology tests, 12-lead electrocardiography, and clinical history, which were conducted within 4 weeks before this study. The study was approved by the Institutional Review Board of Kyungpook National University Hospital (KNUH, Daegu, Republic of Korea) and was conducted at the KNUH Clinical Trial Center in accordance with the applicable Good Clinical Practice guidelines (CRIS registry no.
The safety assessment was based on laboratory and clinical adverse events collected during the red ginseng administration. Vital signs (the heart rate and blood pressure) were monitored at screening, before and after red ginseng administration (at 2, 4, 8, and 12 h after dose).
The safety assessment was based on laboratory and clinical adverse events collected during the red ginseng administration. Vital signs (the heart rate and blood pressure) were monitored at screening, before and after red ginseng administration (at 2, 4, 8, and 12 h after dose). Body temperature was assessed at screening, before and after red ginseng administration (at 2, 4, 8, and 12 h after dose).
대상 데이터
Caco-2 cells [American Type Culture Collection (Rockville, MD, USA); passage number 41-43] were grown in Dulbecco’s Modified Eagle’s medium, supplemented with 20% of fetal bovine serum, 1% of nonessential amino acids, 4 mM of L-glutamine, and 1% of penicillin-streptomycin.
Red ginseng extract (Hong Sam Jung All day; lot no. 731902) was purchased from the Punggi Ginseng Cooperative Association (Youngjoo, Kyungpook, Republic of Korea). Ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, Rg3, Rh1, Rh2, F1, F2, compound K, 20(s)-protopanaxadiol, and 20(s)-protopanaxatriol were purchased from the Ambo Institute (Daejeon, Republic of Korea).
731902) was purchased from the Punggi Ginseng Cooperative Association (Youngjoo, Kyungpook, Republic of Korea). Ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, Rg3, Rh1, Rh2, F1, F2, compound K, 20(s)-protopanaxadiol, and 20(s)-protopanaxatriol were purchased from the Ambo Institute (Daejeon, Republic of Korea). Berberine, used as an internal standard (IS), was purchased from Sigma-Aldrich Chemical Co.
The study included 15 healthy male individuals. The mean age was 24.
이론/모형
Pharmacokinetic parameters were estimated by noncompartmental methods (WinNonlin version 2.0, Pharsight Co., Certara, NJ, USA). The maximum plasma ginsenoside concentration (Cmax) and time to reach Cmax (Tmax) were obtained directly from the results.
The maximum plasma ginsenoside concentration (Cmax) and time to reach Cmax (Tmax) were obtained directly from the results. The area under the plasma concentration-time curve from 0 to the last sampling time was calculated using the trapezoidal method. Half-life (t1/2) was calculated by dividing 0.
성능/효과
1, and the representative MRM chromatograms for the five identified ginsenosides are shown in Fig. 2. Collectively, five ginsenosides and IS peaks were well separated with no interfering endogenous peaks, and the resolution between the peaks of ginsenoside Rb2 and Rc was calculated to be more than 1.2. The concentrations of ginsenosides Rb1, Rb2, Rc, and compound K in plasma were analyzed in the range of 0.
25e100 ng/mL. Interday and intraday precision and accuracy for the analysis of ginsenosides Rb1, Rb2, Rd, Rd, and compound K are shown in Table 3. For interday assays, the precision and accuracy ranged from 2.1 to 12.1% and from 91.1 to 111.4%, respectively (Table 3). In intraday assay validation, the precision and accuracy ranged from 3.
4%, respectively (Table 3). In intraday assay validation, the precision and accuracy ranged from 3.5 to 9.3% and from 87.1 to 109.1%, respectively (Table 3).
The results of the pharmacokinetic analysis revealed that five of 14 ginsenosides (i.e., Rb1, Rb2, Rc, Rd, and compound K) were detected in human plasma samples after oral ingestion of red ginseng extract. Notably, panaxadiol ginsenosides, which are present in high content in red ginseng extract (i.
When comparing the individual plasma concentrations of Rb1, Rb2, Rc, Rd, and compound K, it was noted that Rd and compound K concentrations exhibited substantial variability. Three individuals (participant no. 7-9) showed higher plasma concentrations of Rd and compound K and higher Rd accumulation after red ginseng extract administration than the remaining 12 individuals, suggesting that these three individuals had higher conversion of other ginsenosides into Rd and compound K. Correlation analyses on the pharmacokinetic parameters of Rb1, Rb2, Rc, Rd, and compound K revealed a good correlation between the AUC values of Rd and compound K, independent of the dosing paradigm (i.e., single or repeated administration for 15 days; Fig. 4). These results also suggested the upstream biotransformation of ginsenosides before intestinal absorption, consistent with the previous reports on the intestinal biotransformation of ginsenosides mediated by the gut microbiome [15,21,22].
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