Metabolism of the Total Flavonoid Extract of Lithocarpus litseifolius (Hance) Chun in Rats

The total flavonoid extract of Lithocarpus litseifolius (Hance) Chun (TFLLC), a medicinal and edible plant of the Fagaceae family, has been developed as a preclinical drug candidate in China due to its hypoglycemic effect. The metabolism of TFLLC is closely associated with both its pharmacological activity and potential toxicity. This study investigated the in vitro and in vivo metabolism of TFLLC, which mainly comprises phlorizin and trilobatin. Ultrahigh‐performance liquid chromatography coupled with UV spectrometry and high‐resolution mass spectrometry (UHPLC–UV–HRMS) was used to detect and characterize TFLLC metabolites in rats following oral administration at 50 mg/kg. TFLLC underwent extensive metabolic transformation, and 13 metabolites were identified. The major drug‐related substances included phloretin—derived from glycosidic cleavage of phlorizin and trilobatin—and its conjugated derivatives, such as glucuronidated metabolite M450, sulfated metabolite M354, and dual‐conjugated metabolite M530. These metabolites were primarily excreted in bile and urine. Intestinal incubation studies confirmed that phloretin formation could occur in the gut. These findings provide a pharmacokinetic basis to support the pharmacodynamic interpretation and future drug development of TFLLC.