Abstract
Background and objectives: Ginsenoside compound K (CK) is a candidate drug for rheumatoid arthritis therapy. The objective of this study was to investigate the pharmacokinetic properties, safety and tolerability of CK.Methods: In randomized, double-blind trials, 76 healthy Chinese subjects received 1 of 7 single oral doses (25, 50, 100, 200, 400, 600, 800 mg) of CK or placebo under fasting condition, and another 36 subjects received repeated oral doses (100, 200, or 400 mg) of CK or placebo for up to 9 days a week after a corresponding single dose, after breakfast. Both sexes were equally represented in the two trials. Pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD) were calculated and statistically analyzed according to the plasma concentration data. Tolerability was evaluated by adverse events (AEs) and laboratory examinations.Results: The range of time to maximum concentration (Tmax) was 1.5–6.0 h, with a linear increase in the exposure of CK over the dose range of 100–400 mg. Steady state was reached after the 7th administration, and the accumulation index range was 2.60–2.78. Sex differences were characterized by a higher exposure in females than males with the single administration after breakfast. In addition, no severe AEs were observed.Conclusion: CK was safe and well-tolerated over the treatment period. The sex- and food-related impacts on CK pharmacokinetics need further investigations to be validated. (Registration number: ChiCTR-TRC-14004824 and ChiCTR-IPR-15006107, http://www.chictr.org.cn/index.aspx).
Highlights
Ginsenoside compound K (20-O-beta-D-glucopyranosyl-20(S)protopanaxadiol, known as M1, IH-901, and ginsenosides compound K (G-CK)) belonging to the protopanaxadiol-type saponins (Figure 1) was first isolated by Japanese researchers in 1972 (Yosioka et al, 1972) and could be produced from ginsenosides, such as Rb1, Rb2, and Rc, through various conversion methods (Yang et al, 2015)
The PK parameters, such as Cmax and the area under the curve (AUC), displayed large variations resulting in Sprague Dawley (SD) values that were even larger than half the mean value in this study, indicating that the significant individual difference was at least partly caused by the characteristics of CK
Pharmacokinetics analysis of CK in rats and on Caco-2 cell monolayers conducted by Paek et al suggested that the CK might be mediated through the hepatic uptake transporters (Paek et al, 2006)
Summary
Ginsenoside compound K (20-O-beta-D-glucopyranosyl-20(S)protopanaxadiol, known as M1, IH-901, and G-CK) belonging to the protopanaxadiol-type saponins (Figure 1) was first isolated by Japanese researchers in 1972 (Yosioka et al, 1972) and could be produced from ginsenosides, such as Rb1, Rb2, and Rc, through various conversion methods (Yang et al, 2015). The anti-inflammatory activity of CK has been identified in several studies. Pre-clinical studies suggested that ginsenoside CK had a satisfactory anti-inflammatory effect through significant downregulation of the mRNA levels of tumor necrosis factor (TNF), interleukin 1 (IL1), interleukin 4 (IL4), interferon γ (INFG), and prostaglandin-endoperoxide synthase 2 (PTGS2) (Wang et al, 2016). It has been reported that CK could clearly suppress the activation of mitogenactivated protein kinases (MAPKs) and Toll-like receptors 4 (TLR4)/lipopolysaccharide-induced nuclear factor κB and block pro-inflammatory cytokines secreted by macrophages (Wu et al, 2014). The above results together with the considerable literature available (Cuong et al, 2009; Joh et al, 2011) suggest that CK may be a promising drug for the treatment of rheumatoid arthritis (RA). Ginsenoside compound K (CK) is a candidate drug for rheumatoid arthritis therapy. The objective of this study was to investigate the pharmacokinetic properties, safety and tolerability of CK
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