Medicinal Plant Research 2025, Vol.15, No.4, 169-177 http://hortherbpublisher.com/index.php/mpr 170 contributing to PK and PD response variability, responsible for variability in the efficacy of ginseng between populations (Zhao et al., 2023). This review presents an integrative overview of the recent literature concerning gut microbiota modulation of ginseng pharmacokinetics and pharmacodynamics. It emphasizes microbial transformation of ginsenosides, mechanistic connections between gut microbial metabolism and ginseng pharmacological activity, and implications for personalized medicine. By integrating data from pharmacology, microbiology, and systems biology, this review presents the significance of gut microbiota as a key factor in optimizing ginseng's therapeutic effect and opening the door to its modern clinical use. 2 Major Active Components of Ginseng and Their Pharmacokinetic Characteristics 2.1 Structural features and metabolic stability of ginsenosides Ginsenosides are dammarane type triterpene saponins, mostly categorized as protopanaxadiol (PPD) and protopanaxatriol (PPT) types depending on aglycone structures. The metabolic stability is markedly influenced by the site and number of sugar moieties bonded to the aglycone. Compounds with more residues of sugar are less permeable in membranes and bioavailable, leading to poor oral bioavailability. After oral delivery, the ginsenosides undergo comprehensive biotransformation, primarily deglycosylation by gut microflora, to the metabolites such as compound K with improved bioactivity and bioavailability. Ginsenoside pharmacokinetics is also mediated by drug-metabolizing liver and intestinal liver and intestine transport proteins and interaction with other medications for their efficacy and bioavailability (Won et al., 2018; Ratan et al., 2020; Liu et al., 2024). 2.2 Digestion, absorption, and bioavailability of ginseng polysaccharides Ginseng polysaccharides are high-molecular-weight carbohydrate molecules with strong immunomodulatory, antioxidant, and anti-inflammatory activities. They are size- and structural complexity-constrained to intestinal absorption. Rather, they were partially degraded by gut flora into oligosaccharides and monosaccharides small enough to be absorbed and form systemic actions. Structure–bioactivity correlation is such that uronic acid-containing polysaccharides and specific glycosidic linkages (e.g., α-(1→4)-GalpA) are responsible for their biological activities. Polysaccharide fraction was more immunomodulatory and antiviral in experimental animal models compared to saponin fractions (Hyun et al., 2020; Ji et al., 2020; Park, 2024). 2.3 Pharmacokinetic characteristics of other active components Non-saponin constituents such as volatile oils, polyphenols, peptides, and alkaloids also make a contribution to the pharmacology of ginseng. Volatile oils and polyphenols are more lipophilic overall, and consequently enjoy greater membrane permeability and absorption than do ginsenosides and polysaccharides. Owing to their metabolism and excretion that occurs so quickly, however, their half-lives are typically brief. Peptides and proteins, in low concentrations, have shown defined bioactivities, such as radioprotective and metabolic-modulating effects, but are poorly understood pharmacokinetically due to sensitivity to enzymatic digestion in the gastrointestinal tract (Hong et al., 2020; Dong, 2024). 3 Regulatory Effects of Gut Microbiota on the Pharmacokinetics of Ginseng 3.1 Transformation of ginsenosides by gut microbiota When they are taken orally, the hydrophilic ginsenosides from ginseng are poorly absorbed in their native forms. Gut microflora, particularly such genera as Bacteroides, Eubacterium, and Bifidobacterium, enzymatically metabolize these ginsenosides through deglycosylation. Protopanaxadiol-type ginsenosides like Rb1, for example, are metabolized to more hydrophobic and active metabolites like compound K and ginsenoside Rh2, whereas protopanaxatriol-type ginsenosides are metabolized to Rh1 and protopanaxatriol. These metabolites possess significantly enhanced pharmacological activities, including antitumor, anti-inflammatory, and neuroprotective activities, compared to their parent drugs (Kim, 2017; Zhao et al., 2021). 3.2 Impact of gut microbiota on absorption and bioavailability of ginseng components Gut microbiota-mediated conversion of ginsenosides increases their membrane permeability and systemic absorption, and hence their bioavailability. The density and presence of dominant bacteria have a direct effect on
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