in vivo studies of CK between 2015 and 2020, including hepatoprotective, anti-inflammatory, anti-atherosclerosis, anti-diabetic, anti-cancer, neuroprotective, anti-aging/skin protective, and others. Clinical trial data are minimal and are primarily based on CK-rich fermented ginseng. Besides, numerous preclinical and clinical studies indicating the pharmacokinetic behavior of CK, its parent compound (Rb1), and processed ginseng extracts are also summarized. With the limited evidence available from animal and clinical studies, it can be stated that CK is safe and well-tolerated. However, lower water solubility, membrane permeability, and efflux significantly diminish the efficacy of CK and restrict its clinical application. We found that the use of nanocarriers and cyclodextrin for CK delivery could overcome these limitations as well as improve the health benefits associated with them.
Ginseng (
Panax ginseng) of the Araliaceae family is a perennial plant which has been conventionally used as a functional food. It is commonly consumed as a health supplement in Korea, Japan, China, the United Kingdom, Canada, Germany, France, and Austria . Ginseng’s bioactive constituents, including ginsenosides, phenolic compounds, and polysaccharides, have several medical uses . Ginsenosides (or panaxosides) are the key pharmacologically significant bioactive constituents of ginseng. Nearly 150 ginsenosides isolated from roots, fruits, leaves, flower buds, processed items of ginseng, and other species have been identified. A category of triterpene and saponin ginsenosides are divided into two forms: tetracyclic triterpenoids (four-ring dammarane type) and pentacyclic triterpenoids (five-ring oleanolic type). The dammarane type saponins are further categorized into protopanaxadiol (PPD) and protopanaxatriol (PPT) saponins . The ginsenosides of PPD group constitute Compound K (CK), Rg3, Ra1, Ra3, Ra2, Rh2, Rb1, Rb3, Rb2, F2, Rc, and Rd, while PPT group constitutes of F1, Rg1, Rg2, Rf, Re, and Rh1 . The oleanolic type saponins, such as Ro, are very low in concentration and thus rarely detected. Examples of rare ginsenosides are CK, Rg3, F2, and Rh2, which are either absent in unprocessed ginseng or available at low concentrations [
7]. It is well-known that compared to ginsenosides, their metabolite CK is absorbed well by the body and in lieu of this property, CK is becoming the fast focus of research .
Ginsenoside CK (G-CK; 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol) is a minor tetracyclic triterpenoid, also known as IH901, CK, and M1 . Compound K is absent from natural ginseng and was isolated by researchers from Japan in 1972 by several biotransformation approaches from saponins such as Rc, Rb1, and Rb2 . The various processes used for the CK synthesis include enzymatic use , microbial conversion, heating, mycelial fermentation and metabolic engineering . The detailed procedure of biotransformation has been described in detail elsewhere . Compound K is a major deglycosylated metabolite found in organs or blood after oral ingestion of PPD ginsenosides in the human gastrointestinal (GI) tract (). The molecular weight and chemical formula of CK are 622.86 g/mol and C36H62O8, respectively .
Figure 1. Schematic illustration of plausible biotransformation of major ginsenosides Rb1, Rb2 and Rc to compound K.
A review by Yang et al. described in detail the biotransformation of CK and recorded its pharmacological activities until 2014. Another review compiled information on the biotransformation and pharmacokinetics of CK, including the positive effects on neuroprotection and cognitive improvement by 2016. Like the previously published reviews, this paper documents recent papers targeting hepatoprotective, anti-inflammatory, anti-atherosclerosis, anti-diabetic, anti-cancer, neuroprotective, anti-aging/skin protective effects published from 2015 to 2020. This review, however, differs significantly from previous works, including detailed information on preclinical and clinical pharmacokinetic studies and the inclusion of anti-asthmatic and kidney-protective effects among others in vitro and in vivo activities of CK. Additionally, data are also integrated on several CK derivatives with improved solubility and health-promoting activities.
