Taxifolin (TFL) is a small drug molecule with a broad therapeutic potential limited by its poor aqueous solubility and excessive metabolism. Despite comprehensive research, some aspects of the TFL pharmacokinetics, e.g., dose proportionality and possible cumulative effect, remain unexplored. In the current study, we have tried to fill this gap. Our results revealed that the TFL pharmacokinetics in rats had nonlinear character in the dose range of 10–50 mg/kg after its single oral administration (AUC parameter). For the C_max parameter, the data are ambiguous: linearity was confirmed via the equivalence criterion and was disproved using the power model approach. Also, the cumulative drug effect was observed on the 4^th day after its multiple-dose oral administration (25 mg/kg; compared to the 1^st day). Interestingly, biologically active TFL metabolites such as aromadendrin and luteolin were putatively found in plasma samples, although they were previously detected only in feces. In addition, oil-in-water and water-in-oil microemulsions were fabricated to design novel drug delivery systems. These carrier dosage forms did not improve the TFL bioavailability but significantly affected its metabolism. To support pharmacokinetic studies, the bioanalytical liquid chromatography–tandem mass spectrometry method was developed and validated in the concentration range of 1–1,000 ng/mL using candesartan as an internal standard. Liquid-liquid extraction with methyl tert-butyl ether was used to isolate the analytes from plasma followed by evaporation and reconstitution of the residues in acetonitrile. Thus, the present findings broaden our understanding of the TFL behavior in vivo and provide novel ideas and reference directions for its continued use in medical practice.

紫杉叶素 (TFL) 是一种小分子药物，但由于其水溶性差和代谢过度，其治疗潜力有限。尽管进行了全面的研究，但 TFL 药代动力学的某些方面，例如剂量比例和可能的累积效应，仍未得到探索。在当前的研究中，我们试图填补这一空白。 我们的结果显示，单次口服给药后，TFL在大鼠体内的药代动力学（AUC参数）在10-50 mg/kg剂量范围内具有非线性特征。对于 C _max参数，数据不明确：线性通过等效准则确认，并使用幂模型方法反驳。另外，在多次口服给药后的第4天（25mg ^/  kg；与第1天相比^）观察累积药效。有趣的是，据推测在血浆样本中发现了具有生物活性的 TFL 代谢物，例如芳香树素和木犀草素，尽管以前仅在粪便中检测到它们。此外，还制备了水包油和油包水微乳液来设计新型药物输送系统。这些载体剂型并未提高TFL的生物利用度，但显着影响其代谢。为了支持药代动力学研究，开发了生物分析液相色谱-串联质谱方法，并 使用坎地沙坦作为内标在 1–1,000 ng/mL 的浓度范围内进行了验证。使用甲基叔丁基醚液-液萃取从血浆中分离分析物，然后蒸发并在乙腈中重构残留物。因此，本研究结果拓宽了我们对 TFL 体内行为的理解，并为其在医疗实践中的持续使用提供了新的思路和参考方向。