Mechanisms underlying the promotion of intestinal absorption of baohuoside I by Dipsacus asperoides saponin fractions and their synergistic anti‑osteoporosis efficacy in combination.

Baohuoside I (BA) is the key active ingredient in the compound anti-osteoporosis preparation Xianlinggubao; however, its poor solubility and permeability result in low oral bioavailability. This study systematically investigated, from both pharmaceutical and pharmacological perspectives, the role of Dipsacus asperoides saponins fractions (DAS) in enhancing BA absorption and their synergistic anti-osteoporosis effects. From a pharmaceutical perspective, DAS significantly improves BA's solubility, membrane permeability, and gastrointestinal stability, and forms nanocomposites with BA through noncovalent interactions (as verified by DSC, TEM, FT-IR, and molecular dynamics simulations). In vivo intestinal perfusion experiments in rats confirmed that DAS enhances BA absorption in all intestinal segments; in a Caco-2 monolayer cell model, DAS inhibited MRP2/BCRP efflux and reversibly opened tight junctions, increasing the apparent permeability coefficient of BA from (1.62 ± 0.21) × 10⁻⁶ to (4.25 ± 0.45) × 10⁻⁶ cm/s; Oral pharmacokinetic studies in rats further confirmed that the AUC0-∞ was significantly higher in the BA-DAS combination group. Pharmacologically, in an ovariectomized mouse model, the combination of BA and DAS significantly improved bone microstructure and serum bone metabolism markers compared to BA alone. Urinary non-targeted metabolomics results further revealed that this synergistic effect is associated with the regulation of Ascorbate and aldarate metabolism, Glycine, serine, and threonine metabolism, and Tryptophan metabolism pathways. In summary, DAS promotes BA absorption through a dual mechanism of inhibiting efflux and opening tight junctions, and the combination of BA and DAS produces a synergistic anti-osteoporotic effect, providing a mechanistic explanation for the formulation of traditional Chinese medicine.