In vivo metabolism, pharmacokinetics, and pharmacological activities of ginsenosides from ginseng.

Yuhao Wang: Writing – original draft, Formal analysis, Conceptualization, Investigation. Canglang Mou: Writing – review & editing, Supervision. Yeye Hu: Investigation, Resources, Supervision. Ziliang He: Conceptualization, Investigation, Formal analysis. Jae Youl Cho: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Ji Hye Kim: Writing – review & editing, Supervision, Conceptualization.

Drugs, including ginsenosides, are metabolized in various organs, particularly the gastrointestinal tract and liver, through complex enzymatic and microbial processes. A broader overview of these organ-level metabolic mechanisms—including the roles of gastric acid, gut microflora, and hepatic enzymes—is summarized in Supplementary Information Section 3. The present section focuses on specific in vivo metabolic pathways and the biotransformation of ginsenosides, particularly those of PPT- and PPD-type compounds. High-molecular-weight ginsenosides can only be absorbed by the body once they are broken down by specific enzymes produced by intestinal microorganisms, resulting in low-molecular-weight glycosides or non-glycosides [ 12 ]. Following oral administration, ginsenosides are transformed into several active metabolites through enzymatic actions in the gastrointestinal tract and liver, facilitated by gastric juices, digestive processes, and intestinal microflora. This conversion into bioactive metabolites is essential for the absorption and therapeutic efficacy of ginsenosides [ 13 ]. A study found that following oral administration of red ginseng extract, ginsenoside concentrations in plasma were measured using EIA-HPLC, with the content of Rb1 being nearly undetectable [ 14 ]. Additionally, after administering Rb1 at a dose of 125 mg/kg orally, neither Rb1 nor its intermediate metabolic derivatives were detected in the blood. Only compound K (CK), a metabolite of ginsenoside, was detected, with plasma concentrations ranging from 1.0 to 7.3 μg/mL [ 15 ]. At a dose of 0.8 mg/kg, Rg3 was not detected in plasma [ 16 ]. These findings suggest that the absorption of natural ginsenosides is extremely low, and plasma concentrations are insufficient to elicit pharmacological effects. However, ginsenosides are metabolized and absorbed through a series of hydrolysis reactions after ingestion, with digestive enzymes and bacterial enzymes in the gastrointestinal tract playing crucial roles. The microbiome, a key component of host metabolism, regulates the expression and activity of enzymes involved in drug metabolism [ 17 ]. Essential active compounds such as folate, indole, and gamma-aminobutyric acid are produced through metabolic uptake by the microbiome. The human gastrointestinal tract contains over 2000 microbial species, predominantly from eight major phyla: Firmicutes , Bacteroidetes , Proteobacteria , Actinobacteria , Fusobacteria, Cyanobacteria , and Verrucomicrobia [ 13 ]. Ongoing studies have demonstrated that ginsenosides are transformed into C-K, PPD, and PPT by probiotics such as Bacteroides , Eubacillus , Bifidobacterium , and Fusobacterium , thereby enhancing absorption and increasing the efficacy of ginseng [ 18 ]. While the details of ginsenoside biotransformation in the gastrointestinal tract are not yet fully understood, it is widely accepted that gut flora influences drug metabolism, absorption, and disease progression [ 19 ]. When Rb1 was administered orally at a dose of 200 mg/kg to rats in the absence of microorganisms, no C-K or metabolites were detected in the plasma. The majority of Rb1 remained in the intestine, resulting in low absorption [ 20 ]. Research indicates that deglycosylation and hydrolysis reactions primarily occur in the intestinal microbiota, while enzymatic transformation processes involve only deglycosylation [ 21 ]. Saponins produced by glycosyl hydrolysis are more readily absorbed. Furthermore, ginsenosides are absorbed in the small intestine and subsequently reach the liver, where they undergo extensive metabolism. However, the metabolism of ginsenosides in the liver remains poorly understood. For example, oral administration of ginsenoside Rb1 results in its metabolism by the gut microbiome into compound K, which is then absorbed into the bloodstream and further metabolized into stearic acid-bound compound K in the liver [ 22 ]. Ginsenosides can also be converted into fatty acid esters following intestinal deglycosylation, which contribute to their biological activities. Protopanaxatriol (PPT) is the primary microbial metabolite of protopanaxtriol-type ginsenosides. When orally administered, PPT is absorbed through the small intestine into the mesenteric lymphatic vessels, where it is rapidly esterified into fatty acids that accumulate in the liver [ 23 ]. Cytochrome P450 enzymes play a crucial role in catalyzing the metabolism of PPT [ 24 ]. Among these enzymes, CYP3A4 has been identified as an important isoenzyme involved in the oxygenation metabolism of PPT ginsenosides. Additionally, CYP3A4 is the primary enzyme responsible for the oxidation of Rh2, while alcohol dehydrogenase and aldehyde dehydrogenase are involved in converting alcohol into carboxylic acids [ 25 ]. CYP716A47 catalyzes the oxidation of damalenediol-II to produce protopanaxadiol (PPD). In a study using recombinant WAT21 yeast, ectopic expression of CYP716A47 led to the production of PPD when damalenediol-II was supplied [ 26 ]. In in vivo , naturally occurring ginsenosides encounter substantial challenges in absorption due to their hydrophilic nature, large molecular size, and limited cell membrane permeability, which restricts their bioavailability following oral administration. They undergo sequential deglycosylation catalyzed by glycoside hydrolases (e.g., β-glucosidase, α-rhamnosidase, and xylosidase) produced by gut microbiota, converting these primary ginsenosides into active secondary metabolites [ 27 ]. Transformation of ginsenosides primarily occurs in the gastrointestinal tract [ 28 ]. Under anaerobic conditions with gut bacteria, ginsenosides are converted into various bioactive metabolites, including ginsenoside F1, ginsenoside Rg1, ginsenoside Rg2, and protopanaxadiol (PPT). For PPT-type ginsenosides, deglycosylation preferentially occurs at C-6, with further deglycosylation at C-6 or C-20, ultimately producing PPT as the final metabolite. These transformations enhance the bioavailability and therapeutic efficacy of ginsenosides within the body. Specific metabolic pathways have been mapped for major ginsenosides in the digestive tract. For instance, Rg1, following oral administration, is initially broken down into intermediate metabolites in the stomach and later transformed into ginsenosides F1 and Rh1 in the large intestine within 30 min [ 29 ]. Clinical studies have also detected hydrolysates like Rh1 and F1 in systemic circulation. The metabolic pathways of Rg1 and Re in the digestive system are delineated as follows: Rg1 → F1 or Rg1 → Rh1, and Re → Rg2 → Rh1 or Re → Rg1 → F1 [ 30 ]. Further research by Hasegawa (2004) summarized these pathways for protoginsenosides as: Re → Rg1 → F1 → PPT or Re → Rg1 → Rh1 → PPT. Until 2005, the specific bacterial species responsible for these conversions remained unidentified. However, Bae et al. (2005) provided a breakthrough by isolating enzymes from Bacteroides JY-6 , demonstrating that α-rhamnosidase could transform Re into Rg1, while β-glucosidase converted Re into F1 and PPT via Rg1 [ 31 ]. In addition, Bifidobacterium K-525 was shown to decompose Rg2 into F1, highlighting the significant role of gut microbiota in the metabolic pathways of ginsenosides. Orally administered drugs are typically absorbed in the small intestine and enter the portal circulation, where they travel to the liver and may undergo extensive metabolism. Although limited information is available on the liver metabolism of ginsenosides, some insights have been reported. Once PPT is absorbed and transported to the liver, it is subject to oxidation and glycosylation at the C20 hydroxyl group, facilitated by the enzyme CYP3A4 [ 24 ]. This glycosyl substitution at the C-20 hydroxyl group influences the hepatic clearance rates of ginsenosides, following an order of Rf → Rg2 → Rh1 → PPT, with CYP3A4 playing a major role in this disposition [ 24 ]. The metabolic diagram is shown in Fig. 1 A and Supplementary Table 1 . Fig. 1 Metabolic processes and biotransformation of ginsenosides. (A) The process of converting PPT type ginsenoside into active secondary metabolites under the action of intestinal flora or glycoside hydrolase and other enzymes. (B) The process of converting PPD type ginsenoside into active secondary metabolites under the action of intestinal flora or glycoside hydrolase and other enzymes. This figure was generated by summarizing the information presented in Supplementary Table 1 , which includes all relevant references. Fig. 1 Metabolic processes and biotransformation of ginsenosides. (A) The process of converting PPT type ginsenoside into active secondary metabolites under the action of intestinal flora or glycoside hydrolase and other enzymes. (B) The process of converting PPD type ginsenoside into active secondary metabolites under the action of intestinal flora or glycoside hydrolase and other enzymes. This figure was generated by summarizing the information presented in Supplementary Table 1 , which includes all relevant references. In the intestines, Rb1, Rb2, and Rc are gradually broken down through glycolysis to produce the metabolites CK and PPD. For PPD-type ginsenosides, the deglycosylation process begins at the C-3 position, with further deglycosylation at either C-3 or C-20, yielding the primary bioactive compound, PPD [ 32 ]. Studies in animal models have provided insights into this metabolic process. For instance, Odani and colleagues demonstrated that in rats, orally administered Rb1 undergoes considerable breakdown in the digestive tract. After 4 h, it begins to decompose in the stomach, producing an initial metabolite, and then further transforms in the large intestine into ginsenoside Rd and two unidentified metabolites [ 29 ]. During this metabolism process, Rb1 rapidly degrades within an hour, while Rd emerges as a subsequent metabolite. Over time, Rd gradually transitions to F2 and eventually to compound K, with compound K levels notably rising after approximately 8 h as Rd diminishes [ 33 ]. Similarly, Rb2 also undergoes decomposition in the large intestine, yielding products such as Rd, compound O, ginsenoside F2, compound Y, and compound K [ 34 ]. Bae and colleagues further extended these findings by identifying bacterial species responsible for ginsenoside metabolism. They found that Eubacterium sp., Streptococcus sp., and Bifidobacterium sp. specifically detect and degrade Rb1, while Bacteroides sp. and Clostridium K-60 facilitate the transformation of Rd to compound K [ 35 ]. Likewise, Rb2 undergoes a similar decomposition process, involving bacteria such as Eubacterium, Streptococcus, Bifidobacterium, and Clostridium K-60, which convert it through Rd and O into compound K. Compound K is regarded as one of the primary bioactive metabolites, exhibiting diverse pharmacological applications, including organ protection, cognitive support, neuroprotection, antioxidation, anti-cancer, anti-proliferative, and anti-diabetic effects [ 36 ]. Upon further metabolism, compound K is broken down to PPD by Eubacterium sp., Bifidobacterium sp., and Bacteroides sp [ 37 ]. Ginsenoside Rc, which shares a structural similarity with Rb1 and Rb2, also undergoes hydrolysis by human gut bacteria into CK and PPD. Specifically, Rc is decomposed into CK via Rd by K-103 Bifidobacterium and A-44 Eubacterium and through ginsenoside Mb by Bacteroides HJ-15 and K-506 Bifidobacterium. BAE and colleagues delineated two metabolic pathways for Rc: (1) Rc → Rd → F2 → CK → PPD, and (2) Rc → Mb → Mc → CK → PPD [ 38 ]. Another member of the protopanaxadiol ginsenoside family, Rg3, is metabolized by Bacteroides, Bifidobacterium, and Fusobacterium to yield Rh2 [ 35 ]. Hasegawa later summarized these metabolic pathways, indicating the sequential transformation of Rb1 to Rd, then to F2, and ultimately to CK, or through an alternative route involving gypenoside intermediates. Likewise, Rb2 follows a pathway through compounds O and Y before forming CK, while Rc proceeds through Mb and Mc before reaching CK [ 39 ]. The intestinal metabolites CK and PPD play a critical role in the biological effects of protopanaxadiol ginsenosides. They are partly excreted in feces, while the remaining portion is absorbed through the small intestine into systemic circulation [ 40 ]. Previous studies have demonstrated that after intravenous administration of CK in mice and rats, CK quickly exits the bloodstream and selectively accumulates in the liver, where it undergoes oxidation by enterohepatic cytochrome P450 enzymes [ 41 ]. The diagram of these metabolic pathways is presented in Fig. 1 B, and further details can be found in Supplementary Table 1 .

Ginseng, widely used for health and therapeutic purposes since ancient times, owes much of its efficacy to ginsenosides, a class of triterpenoid saponins that serve as its key active compounds. Ginsenosides exhibit diverse activity levels, with increasing evidence suggesting that their deglycosylated forms offer significantly enhanced bioactivity. Studies reveal that ginsenosides undergo progressive decomposition into various forms through the action of enzymes and certain bacteria, such as lactic acid bacteria, which are frequently used to convert major ginsenosides into their more active, deglycosylated counterparts. Given that ginseng is typically consumed as a decoction, researchers have been particularly interested in the metabolism of ginsenosides within the body. A thorough understanding of ginsenoside metabolism in vivo is essential to fully grasp their pharmacological benefits, as well as to determine their pharmacologic toxicity and therapeutic dosages. This review primarily examined the classification, concentrations, and pharmacokinetic characteristics of ginsenosides, along with their metabolic pathways. By highlighting the distribution of ginsenosides following ginseng intake and metabolism, we sought to clarify their in vivo pharmacological effects and dosage parameters used in studies. These insights are intended to support further research on the medicinal potential of ginsenosides and to guide future developments in drug formulation.

Ginsenosides are the major pharmacologically active components of ginseng, classified by aglycone structure into dammarane- and oleanane-type saponins. Details on classification, representative structure, and biosynthetic characteristics are provided in the Supplementary Information Section 2. Ginsenoside profiles differ significantly depending on processing methods, ginseng part, and extraction conditions. A comparative summary of key ginsenosides in white, red, and water-extracted ginseng is available in the Supplementary Information Section 2.1. Heat processing alters the polarity and structure of ginsenosides via deglycosylation, dehydration, and decarboxylation. Transformation pathways and associated structural changes are described in detail in the Supplementary Information Section 2.2.

Ginseng, classified under the Panax acanthaceae genus, is widely recognized for its potent pharmacological activity, particularly in East Asia [ 1 ]. With over 10 ginseng species identified, three stand out for their therapeutic applications: P. ginseng (Korean ginseng), P. quinquefolius (American ginseng), and P. notoginseng (Chinese ginseng) [ 2 ]. Boasting a history spanning more than 2000 years, ginseng has emerged as a prominent medicinal plant with beneficial effects on various diseases. In Korea, China and Japan, ginseng is regarded as the most important herb [ 3 ]. As early as the 18th century, the efficacy of ginseng has been known in the West, and the research on ginseng has a long history. Contemporary medical research supports the notion that ginseng exerts regulatory effects on a myriad of disorders, as evidenced by studies demonstrating its anti-diabetic, anti-depressant, anti-inflammatory, and anti-tumor properties [ 4 ]. The diverse pharmacological activities of ginseng are attributed to its rich array of active ingredients, including ginsenosides, polysaccharides, volatile oils, glycopeptides, amino acids, and vitamins [ 4 , 5 ]. However, most of the pharmacological effects of ginseng are attributed to ginsenosides [ 6 ]. Research has demonstrated that ginsenosides play a critical role in various biological processes, including wound healing, anti-inflammatory responses, anti-diabetes effects, and cognitive impairment [ [7] , [8] , [9] , [10] ]. Unfortunately, the majority of ginsenosides are not readily absorbed directly; instead, they are absorbed through a stepwise metabolism facilitated by the intestinal microbiota. The gut microbiota exhibits a variety of physiological activities, mainly including the ability to metabolize foreign organisms for oral and biliary secretion [ 11 ]. The gut microbiota converts components of oral hydrophilic drugs and phytochemicals, which are then absorbed into the bloodstream by the gastrointestinal tract. Studying the in vivo metabolism of ginsenosides is crucial for gaining a deeper understanding of their biological effects. Therefore, this review summarizes the pharmacokinetics of ginsenoside, metabolism in vivo , and the pharmacological activities of each metabolite.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ginseng, traditionally used for thousands of years in East Asian medicine, is particularly well known for its role in invigorating spleen qi deficiency (SQD) [ 54 ]. In traditional Chinese medicine, qi refers to the vital life force that sustains physiological functions and maintains immune balance. Among the internal organs, the spleen is believed to regulate digestion and nutrient transport, while the lung governs respiration and protective immunity—both of which are closely tied to qi circulation. A deficiency in spleen qi is thought to impair these functions, often manifesting as fatigue, digestive disturbance, and susceptibility to illness [ 55 ]. The exploration of ginseng's active constituents has been driven by these traditional therapeutic claims, with particular focus on ginsenosides—its major pharmacologically active components known to exhibit diverse biological effects [ 56 ]. Extensive research indicates that ginsenosides can modulate glycolysis, lipid metabolism, mitochondrial function, and oxidative stress, showing their potential in treating various diseases [ 57 ]. In particular, ginsenosides have demonstrated promising therapeutic effects in cancer, cardiovascular disease, diabetes, Alzheimer's disease, and inflammation [ 58 ]. However, some ginsenosides have low bioavailability, and after metabolism in vivo , it was found that the metabolized ginsenosides have stronger pharmacological activity and improve bioavailability. The multifaceted impact of ginsenosides on these conditions underscores their potential as valuable agents in disease management. This research contributes to the growing body of evidence supporting the efficacy of ginsenosides in addressing diverse health challenges. The pharmacological activities and dosage of ginsenosides as determined through in vitro and in vivo studies are shown in Supplementary Table 3 and Fig. 2 . Fig. 2 Pharmacological activity of ginsenosides metabolites in vivo . The content was compiled from Supplementary Table 3 , where all corresponding references are listed. Fig. 2 Pharmacological activity of ginsenosides metabolites in vivo . The content was compiled from Supplementary Table 3 , where all corresponding references are listed. Re, a water-soluble compound constituting 23 % of total saponins, has garnered attention for its diverse pharmacological activities, encompassing anti-diabetic, neuromodulatory, anti-inflammatory, and anti-cancer effects [ 59 ]. Previous research by Zhang et al. has demonstrated that Re, administered at 40 mg/kg intraperitoneally for 2 weeks, effectively ameliorates insulin resistance by inhibiting c-Jun N-terminal kinase (JNK) and nuclear factor NF-κB activation [ 60 ]. Furthermore, oral administration of Re at 20 mg/kg for 2 weeks regulates insulin levels, improves lipid metabolism, and mitigates endothelial cell dysfunction through the modulation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2, and JNK pathways [ 61 ]. Studies have indicated that Re administration at 20 mg/kg intraperitoneally for 2 weeks offers neuroprotective effects against methamphetamine-induced dopaminergic neurotoxicity. This neuroprotection is associated with reduced oxidative burden through protein kinase Cẟ (PKCδ) gene inactivation, compensatory induction of glutathione peroxidase (GPx) activity, mitochondrial dysfunction, pro-inflammatory changes, apoptotic cell degeneration, and dopaminergic degeneration [ 62 ]. Additionally, in the context of LPS-induced systemic inflammation, Re, administered orally at 10 and 20 mg/kg for 4 h, suppresses serum levels of IL-1β and TNF-α in mice. Re also prevents NF-κB activation and MAPK inhibition and retains activation of the estrogen receptor and PI3K/Akt signaling pathway in LPS-induced myocardial inflammation in mice [ 63 ]. In tumor research, intraperitoneal administration of Re at 5 and 10 mg/kg for 1 week demonstrates the ability to improve bone marrow suppression induced by cyclophosphamide. This intervention reduces clinical symptoms of bone marrow suppression and promotes the recovery of bone marrow hematopoietic function [ 64 ]. The cumulative evidence underscores the multifaceted therapeutic potential of Re in various physiological and pathological conditions. Ginsenoside Rf, a protopanaxtriol-derived glycoside originating from ginseng, has demonstrated notable anti-inflammatory effects in various in vivo and in vitro models [ 65 ]. Qin's research has specifically highlighted the anti-inflammatory properties of ginsenoside Rf, showing its ability to down-regulate the activation of specific pro-inflammatory cytokines and pathways. This modulation is implicated in the developmental processes associated with endometriosis [ 66 ]. The findings contribute valuable insights into the potential therapeutic applications of ginsenoside Rf, particularly in addressing inflammatory aspects related to endometriosis. Studies have also shown that Rf can effectively relieve pain hypersensitivity in neuropathic pain rat models, as well as reduce neuropathic pain and its associated depression by restoring pro-inflammatory and anti-inflammatory cytokines [ 67 ]. Ginsenoside Rg1 (Rg1), a prominent propanaxtriol saponin found in ginseng products, has been the subject of extensive research regarding its antidiabetic activity, with a primary focus on its regulatory effects on insulin signaling pathways [ 68 ]. Notably, studies have indicated that Rg1 effectively prevents hyperglycemia in high-fat diet (HFD)-fed mice by activating AKT, facilitating the interaction between AKT and FoxO1, and suppressing hepatic glucagon response [ 69 ]. Furthermore, Rg1 has demonstrated neuroprotective effects in the context of ischemia/reperfusion-induced neuronal damage by modulating the Nrf2/antioxidant response element (ARE) signaling pathway through the regulation of miR-144 [ 70 ]. Additionally, another ginsenoside, Rg2 (administered at 20 mg/kg), has shown promise in alleviating depression by down-regulating GAS5 expression, thereby reducing microglial activation and improving mitochondrial dysfunction [ 71 ]. These findings collectively suggest that Rg1 holds significant potential in addressing nervous system diseases, implying its potential role in therapeutic interventions for such conditions. The multifaceted pharmacological effects of Rg1 underscore its importance in exploring novel treatment approaches for disorders related to the nervous system. Ginsenoside Rg2, a protopanaxtriol (PPT) saponin, exhibits robust antioxidant capabilities and exerts various physiological effects, enhancing cardiovascular function and overall body function [ 72 ]. Notably, Rg2 treatment (10 mg/kg, intraperitoneally administered once a day for 4 weeks) significantly mitigates intracellular lipid deposition and oxidative stress in primary mouse hepatocytes induced by oleic and palmitic acid (OA&PA) in a manner dependent on SIRT1 activation [ 73 ]. Moreover, when administered intragastrically at 20 mg/kg daily for 28 days, Rg2 alleviates myocardial fibrosis and improves cardiac function following myocardial ischemia by inhibiting the TGF-β1/Smad signaling pathway. Numerous studies have highlighted the notable effects of Rg2 on the nervous system. Rg2 has been shown to improve cognitive impairment and reduce hippocampal Aβ deposition in mice with Alzheimer's disease by modulating oxidative stress response, protecting against glutamate-induced neurotoxicity, and preserving blood vessel memory impairment [ 74 ]. Additionally, Rg2 administration (10 and 20 mg/kg for 4 weeks) has been demonstrated to delay brain aging by enhancing mitochondrial autophagy flux and maintaining mitochondrial function [ 75 ]. These findings collectively underscore the versatile and beneficial effects of Rg2 across various physiological systems, emphasizing its potential therapeutic significance. Rh1, identified as a major ginsenoside in red ginseng, undergoes significant hydrolysis or metabolism from protopanaxtriol ginsenosides following the oral administration of ginseng extract, particularly within the gastrointestinal tract [ 52 ]. Numerous investigations have demonstrated the diverse pharmacological effects of Rh1, encompassing neuroprotection, potential antitumor activity, and therapeutic potential in chronic inflammatory diseases [ 76 ]. In a pivotal study, Jin et al. provided evidence that Rh1 effectively impedes PMA-mediated lung inflammation by intricately inhibiting the phosphorylation and nuclear translocation of MAPK, Akt, and NF-κB [ 77 ]. Furthermore, pertinent research has validated Rh1's ability to restrain tumor growth, with oral administration of ginsenoside Rh1 at a dosage of 20 mg/kg demonstrating significant inhibition of gastric cancer growth through the regulation of the TGF-β/Smad pathway [ 75 ]. Besides, Rh1 can reduce liver injury by inhibiting the activation of Akt/FoxO1 signaling pathway induced by T2DM, inhibiting the increased secretion of G6Pase and PEPCK in gluconeogenic pathway, and inhibiting inflammatory factors including NF-κB and NLRP3 [ 78 ]. These findings contribute substantially to the scholarly understanding of Rh1's multifaceted pharmacological profile, emphasizing its potential in mitigating inflammation and influencing pathways associated with tumorigenesis. Ginsenoside Rb1 (Rb1), one of the most abundant ginsenosides, exhibits neuroprotective effects against ischemic brain injury due to its anti-inflammatory, antioxidant, and anti-apoptotic properties [ 79 ]. In the study by Ni et al., it was reported that Rb1 inhibits astrocyte reactivity by blocking the production of RET-ROS, preserving mitochondrial integrity, facilitating the transfer of functional mitochondria from astrocytes to neurons, ultimately contributing to the protection of neurons from ischemic damage [ 80 ]. Furthermore, Rb1, administered intraperitoneally at a dosage of 60 mg/kg daily for 12 days, effectively mitigates the high-fat diet (HFD)-induced increase in fasting blood glucose (FBG), impaired glucose tolerance, and reduced insulin sensitivity in HFD-induced type 2 diabetes mellitus (T2DM) mouse models [ 81 ]. Rb1 improves calcium deposition and osteogenic transdifferentiation of VSMC both in vivo and in vitro . Rb1 therapy mitigated vascular calcification by activating peroxisome proliferation-activated receptor-γ (PPAR-γ) to inhibit the Wnt/β-catenin pathway [ 81 ]. These findings underscore the significant potential of Rb1 in improving both neurological and metabolic aspects associated with ischemic brain injury and T2DM, respectively. Ginsenoside Rb2 (Rb2) has been the subject of multifaceted pharmacological investigations, demonstrating a comprehensive impact on conditions such as diabetes, obesity, tumors, photoaging, viral infections, and cardiovascular issues [ 82 ]. Recent research has expanded the understanding of Rb2's pharmacological activities, revealing additional benefits in various health domains. Osteoporosis, a common condition in modern health, has been studied in the context of ginsenoside Rb2, which at a dosage of 18 μmol/kg, effectively counteracts estrogen deficiency-induced osteoporosis by reducing reactive oxygen species and oxidative stress levels [ 83 ]. Furthermore, Rb2, given intraperitoneally at 40 mg/kg, has been found to reduce fat accumulation, enhance glucose metabolism, and alleviate insulin resistance through the activation of AKT signaling pathways [ 84 ]. In the context of rectal cancer, Rb2 administered at 5 mg/kg intraperitoneally demonstrated anti-metastatic effects in an EGFR/SOx2-dependent manner. This intervention significantly diminishes the number of metastatic nodules in the liver, lungs, and kidneys, highlighting the potential of Rb2 in antagonizing rectal cancer progression [ 85 ]. These findings contribute to the expanding knowledge of Rb2's diverse pharmacological effects and suggest its potential utility in addressing various health conditions. Ginsenosides Rc is one of the main propanaxanadiol saponins isolated from ginseng, a well-known herb with many beneficial effects such as anti-NAFLD [ 86 ], anti-inflammatory [ 87 ], anti-obesity and anti-diabetes [ 86 ]. In a study by Pan et al., it was demonstrated that the administration of ginsenoside Rc upregulates SIRT6-NRF2 interactions, consequently mitigating alcohol-induced oxidative stress. This protective effect is associated with improvements in Alcoholic Liver Disease ( ALD) [ 85 ]. Furthermore, Rc exhibits notable regulatory effects in the realm of cardiovascular diseases. Administering Rc orally at 20 mg/kg induces SIRT1 activation, reducing mitochondrial oxidative stress and apoptosis through FOXO1 deacetylation [ 88 ]. Additionally, Rc plays a pivotal role in the regulation of metabolic diseases, particularly in the context of type 2 diabetes mellitus (T2DM), a substantial health concern associated with cardiovascular complications. Relevant studies indicate that ginsenoside Rc, when administered orally at 20 mg/kg, enhances endothelial insulin sensitivity by upregulating angiotensin-converting enzyme 2. This suggests the promising potential for the clinical application of ginsenoside Rc in treating diabetic vascular complications [ 89 ]. These findings contribute to the scientific understanding of ginsenoside Rc's diverse pharmacological effects, indicating its potential therapeutic utility in ALD, cardiovascular diseases, and T2DM-related complications. Research findings indicate that Rd, administered orally at a dosage of 10 mg/kg, exhibits preventive effects against skeletal muscle depletion associated with aging and cancer. This effect is attributed to Rd's binding to STAT3, resulting in enhanced muscle function and the inhibition of protein-degrading factors such as MSTN, atrogin-1, and MuRF-1 [ 90 ]. Moreover, Rd plays a crucial role in cardiovascular diseases. Zhang et al. demonstrated that oral administration of Rd at 50 mg/kg normalizes NO signaling through TLR4/MyD88/NF-κB/iNOS and AGTR1/eNOS pathways, thereby safeguarding the aorta from endothelial damage. Additionally, Rd, administered orally at 40 mg/kg, induces mitochondrial autophagy by activating the AMPK/ULK1/p62 signaling pathway, leading to the reversal of mitochondrial membrane potential collapse. This, in turn, inhibits the NLRP3 inflammasome, effectively alleviating DSS-induced colitis [ 91 ]. These findings contribute valuable insights into the multifaceted pharmacological effects of Rd, emphasizing its potential therapeutic applications in mitigating skeletal muscle depletion, cardiovascular disorders, and inflammatory conditions. Previous studies have found that Rg5 has multiple pharmacological effects, including muscle regeneration [ 92 ], anti-inflammatory [ 93 ], antidiabetic [ 94 ] and neuroprotective [ 95 ] properties. Kim et al. found that Rg5 (0.061 mg/kg) reduces cecal ligation and double puncture (CLP)-induced mortality and pulmonary injury [ 96 ]. Rg5 attenuates oxidative stress and inflammatory states in HFD/STZ-induced DN mice by inactivating p38 MAPK and NF-κB signaling pathways [ 97 ]. Rg5 exerts sedative and hypnotic effects by affecting GABA and serotonin signaling [ 98 ]. Rg5 alleviates cognitive dysfunction in streptozotocin (STZ)-induced Alzheimer's disease (AD) rats by regulating cholinergic signaling, attenuating Aβ deposition and increasing neurotrophic factor expression [ 99 ]. Rg5 protects mitochondrial morphological and functional integrity by regulating HK-II and Drp1 translocation via Akt activation [ 100 ]. Rg5 prevents destruction of articular cartilage via inhibition of chondrocyte apoptosis and matrix damage in osteoarthritis rats [ 101 ]. Rg5 inhibits succinate-associated lipolysis and prevents insulin resistance by reducing lipid deposition [ 101 ]. Ginsenoside Rg3, one of the key metabolites formed during the steaming process of red ginseng, has been widely studied for its pharmacological potential. Its activities have been demonstrated across various disease models, particularly in inflammation, oxidative stress, cancer, and metabolic disorders. A detailed summary of the biological effects and mechanisms of Rg3 is provided in Supplementary Information Section 5.11. Compound K (CK), a major metabolite produced through intestinal microbial deglycosylation of protopanaxadiol-type ginsenosides, exerts a wide range of pharmacological effects. These include anticancer, anti-inflammatory, immunomodulatory, and hepatoprotective activities, among others. Further mechanistic insights and supporting data are described in Supplementary Information Section 5.12.

Various studies have investigated the pharmacokinetics of ginsenosides. Dong et al. identified multiple ginsenosides, including Re, Rg1, Rf, Rb1, Rc, Rg2, Rb2, Rd, F1, F2, and compound K, in rat plasma following oral administration of ginseng extract. Their findings showed that among these, ginsenoside Rg2 exhibited the longest half-life, while compound K demonstrated the highest Tmax, Cmax, and AUC [ 42 ]. Zhou et al. conducted the initial study on the pharmacokinetic characteristics of ginsenosides Rg5, Rh4, Rk1, and Rk3 following oral administration of red ginseng (RG) water extract. Although these ginsenosides are present in lower concentrations in RG water extract compared to Rb1 and Rg1, their systemic exposure levels were still relatively substantial. Conversely, certain ginsenosides—such as Ra1, Ra3, Rs1, and Rs2—were not detected in rat plasma, likely due to their minimal concentrations in RG water extract combined with inherently low bioavailability [ 43 ]. Pharmacokinetic differences have been reported between glycosylation levels and among the PPD and PPT ginsenoside types [ 44 ]. Deglycosylated metabolites, in particular, show greater absorption into the bloodstream and often represent the bioactive forms. For instance, the bioavailability of ginsenosides Rb1, Rb2, and Rd is less than 5 % in rats, while PPD exhibits a significantly higher bioavailability of 36.8 % [ 45 ]. Furthermore, following oral administration of red ginseng water extract in rats, Tmax values differed by glycoside structure: monosaccharide ginsenosides (e.g., Rh1, Rk3, and Rh4) had Tmax values from 0.5 to 3 h, disaccharide ginsenosides (such as Rg1, Rg2, Rg3, Rf, R2, Rk1, and Rg5) reached Tmax between 1 and 6 h, and trisaccharide and tetrasaccharide ginsenosides (including Re, Rd, Rc, Rb1, and Rb2) had Tmax values ranging from 2 to 8 h. These patterns indicate that additional sugar moieties reduce both absorption and elimination rates [ 43 ]. Additionally, studies by Li, Xu, and colleagues explored the absorption profiles of PPD- and PPT-type ginsenosides in rats, revealing distinct pharmacokinetic properties. For instance, ginsenoside Rb1 showed a Tmax of 1.5 h with a bioavailability ranging from 1.2 % to 4.3 %, while ginsenosides Rg1 and Re displayed shorter Tmax values (1 h) and higher bioavailability levels of 18.4 % and 7.1 %, respectively. These results indicate that Rg1 and Re are absorbed both more rapidly and in greater quantities than Rb1 [ 46 ]. Furthermore, additional studies consistently indicate that PPT-type ginsenosides generally possess higher oral bioavailability than PPD types, likely due to the slower metabolic transformations characteristic of PPT ginsenosides [ 46 ]. Numerous studies have examined the pharmacokinetic differences between parent ginsenosides and their metabolites. One study on Korean Red Ginseng extract analyzed the pharmacokinetics of ginsenoside Rb1 and its metabolite, compound K, in human plasma. Findings indicated that compound K reached a significantly higher mean maximum plasma concentration (Cmax) of 8.35 ± 3.19 ng/mL compared to Rb1's Cmax of 3.94 ± 1.97 ng/mL. However, Rb1 exhibited an area under the plasma concentration-time curve (AUC) and half-life approximately seven times greater than those of compound K. No correlation was identified between the Cmax and AUC of Rb1 and CK, indicating that the absorption levels of Rb1 and CK were independent [ 27 ]. Meanwhile, the Tmax of Rb1 and CK were 8.70 ± 2.63 h and 12.20 ± 1.81 h, respectively, and a significant correlation was confirmed between the Tmax of Rb1 and CK. The longer Tmax for CK suggests that its pharmacokinetic profile may be influenced by the intestinal microbial conversion of Rb1 to CK [ 27 ]. Additionally, in a separate study, six ginsenoside metabolites—Rh2, 20(S)-PPT, 20(R)-PPT, PPD, Rh3, and compound K—were monitored in rat plasma, with most metabolites first appearing between 2 and 4 h after administration and reaching their Cmax within 6–12 h. Among these, Rh2 and PPD displayed notably high systemic exposure, similar to the levels observed for their precursor ginsenosides, Rb1 and Rd [ 43 ]. Several studies have highlighted that the plasma concentrations of compound K vary depending on the type of ginseng product used. For example, Fukami et al. (2019) reported that fermented ginseng extract resulted in a plasma concentration of compound K that was over 35 times higher than that observed after administering non-fermented ginseng extract [ 47 ]. Similar differences in the pharmacokinetic properties of ginsenosides, influenced by the processing method of ginseng, were discussed by Chen et al. Their review compared the pharmacokinetic profiles and tissue distribution of white ginseng (WG), frozen ginseng (FG), and RG, noting that the area under the curve (AUC) for G-Rg1, G-Re, G-Rb1, and G-Rd was higher in the extract than for the pure ginsenosides. Moreover, these pharmacokinetic parameters differed based on the processing method. The Tmax values for Rg1, Re, Rb1, and Rd were shorter in rats administered the RG extract compared to those administered FG or WG extracts, or the pure ginsenosides. Additionally, the concentrations of G-Rg1, G-Re, G-Rb1, and G-Rd in tissues were higher following the RG extract administration compared to the pure ginsenosides. However, the underlying mechanisms responsible for these differences in pharmacokinetics have yet to be fully elucidated [ 48 ]. Liu et al. compared the pharmacokinetic profiles of Panax ginseng decoction (GD) and total ginsenosides aqueous solution (TGAS) and found significant differences in the pharmacokinetic parameters of ginsenosides Rb1, Rc, and Rd. Notably, the absorption and bioavailability of Rb1 were greater following GD administration compared to TGAS. Additionally, the biotransformation of Rb1 and Rc was more pronounced with GD than with TGAS. For Rd, plasma concentrations after TGAS administration were too low to calculate pharmacokinetic parameters, whereas values for Rd were successfully obtained following GD administration. Despite GD containing a higher polysaccharide content than TGAS, the metabolic pathways for the ginsenosides were similar between the two formulations. These findings suggest that the polysaccharides in GD did not significantly influence the biotransformation process, although the observed differences in pharmacokinetic parameters may be attributed to the polysaccharide composition of the ginseng decoction [ 49 ]. In human studies, compound K was identified in the bloodstream approximately 24 h following oral administration of ginseng, with average pharmacokinetic parameters reported as follows: Tmax of 10.76 ± 2.07 h, Cmax of 27.89 ± 24.46 ng/mL, and AUC of 221.98 ± 221.42 μg h/mL [ 50 ]. In another investigation involving healthy subjects, the pharmacokinetics of various ginsenosides were assessed after single and repeated doses of red ginseng extract (Hong Sam Jung All Day; lot no. 731902) administered over 15 days [ 51 ]. Following ginseng extract administration, Rb1, Rb2, Rc, Rd, and compound K were detected in plasma, whereas PPT-type ginsenosides such as Re, Rh1, and Rg1 were absent. Repeated dosing resulted in notable accumulation of Rb1, Rb2, Rc, and Rd in plasma, with accumulation factors of 4.55, 6.73, 5.44, and 4.49, respectively. In contrast, compound K displayed a low accumulation factor of 0.85, likely attributed to its relatively short half-life. Although previous studies have explored the influence of Rb1 on plasma compound K concentrations [ 52 ], this study uniquely identified a correlation between the AUC values of Rd and compound K. These findings underscore the importance of the intestinal biotransformation pathway in the pharmacokinetics of ginsenosides, with sequential conversion from Rb1, Rb2, and Rc to Rd, and subsequently to compound K, playing a key role in their observed pharmacokinetic behavior [ 51 ]. In humans, the pharmacokinetic profiles of Rb1, Rg3, Rg5, Rk1, F2, and CK were also evaluated following a single oral dose of RG and bioconverted red ginseng (BRG). Results indicated that Cmax, AUC (0–t), and AUC (0–∞) values for these ginsenosides were significantly higher after BRG administration compared to RG. Additionally, the Tmax for compound K was notably shorter with BRG, suggesting an accelerated absorption rate for bioactive ginsenosides through BRG administration [ 53 ]. The pharmacokinetic parameters of ginsenosides in blood and tissues are presented in Supplementary Table 2 .

No data was used for the research described in the article.