Study on the influence of gut microbiota on the pharmacokinetics of Huoxiang Zhengqi oral liquid in rats.

چکیده اصلی

Huoxiang Zhengqi oral liquid (HXZQ), a classical herbal formulation used for gastrointestinal disorders, contains multiple bioactive constituents whose in vivo disposition remains incompletely understood. This study examined the role of gut microbiota in the biotransformation and pharmacokinetics of representative HXZQ constituents using integrated in vitro and in vivo approaches. Anaerobic incubation with gut microbiota was first used to assess metabolic susceptibility. A validated high-performance liquid chromatography-tandem quadrupole mass spectrometry (HPLC-QQQ-MS/MS) method was then developed for simultaneous quantification of 12 representative constituents. Pharmacokinetic profiles were subsequently compared in portal and systemic plasma after oral administration of HXZQ to normal and pseudo-germ-free (PGF) rats. The constituents exhibited heterogeneous microbiota-dependent metabolism. Flavonoid glycosides and triterpenoid saponins, including liquiritin apioside, liquiritin, glycyrrhizic acid, hesperidin, and narirutin, underwent extensive microbial transformation, with transient formation of corresponding aglycones. In contrast, lignans and coumarins showed limited conversion. Pharmacokinetic analysis showed that gut microbiota significantly influenced portal and systemic exposure of several constituents. In PGF rats, exposure to key aglycones, including 18-β-glycyrrhetinic acid, isoliquiritigenin, and liquiritigenin, was markedly reduced, whereas exposure to parent glycosides, such as glycyrrhizic acid, increased. Some compounds were detected in portal plasma but not systemic plasma, indicating limited systemic availability. Moreover, magnolol and byakangelicin exposure was significantly decreased in PGF rats despite weak direct microbial susceptibility in vitro. These findings indicate that HXZQ pharmacokinetics is strongly shaped by microbiota-dependent metabolism and post-absorption disposition, providing insight into host-microbiota-herb interactions.

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