Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR). The results indicated that the thiol of GSH or Cys can be reacted with the exomethylene carbon atoms of α, β-unsaturated carbonyl of AL and IAL. After intravenous administration in rats, AL and IAL were extensively metabolized, and the exposure, as measured by area under the concentration-time curve (AUC), for AL-GSH, AL-Cys, IAL-GSH, and IAL-Cys was approximately 1.54-, 0.96-, 1.50-, and 0.91-fold that of the parent drug, respectively. The AUC ratio of metabolites to parent compounds of oral administration was 3.66-, 9.19-, 12.97-, and 9.92-fold that of the parent drug for the above metabolites, respectively. The bioavailability of AL-total (AL, AL-GSH, AL-Cys) and IAL-total (IAL, IAL-GSH, IAL-Cys) was, respectively, 8.39% and 13.07%, which was 3.62- and 6.95- fold that of AL (2.32%) and IAL (1.88%), respectively. The oral exposure will be underestimated if the parent drugs are tested alone. These findings provide useful information for preclinical safety evaluation, and for predicting AL and IAL metabolism in humans.

从菊苣提取物中分离出的两种主要的倍半萜烯内酯是丙内酯（AL）和异戊内酯（IAL），具有广泛的药理活性。在体外观察到的AL和IAL的主要代谢途径是谷胱甘肽（GSH）共轭，这可能是在没有代谢酶的情况下发生的。还可以观察到半胱氨酸（Cys）的非酶结合。随后分离出四种代谢物（AL-GSH，AL-Cys，IAL-GSH，IAL-Cys）并通过核磁共振（NMR）确认。结果表明，GSH或Cys的硫醇可与AL，IAL的α，β-不饱和羰基的外亚甲基碳原子反应。在大鼠中静脉内给药后，AL和IAL被广泛代谢，并且通过浓度-时间曲线（AUC）下的面积测量，AL-GSH，AL-Cys，IAL-GSH和IAL-Cys的暴露约为分别是母体药物的1.54倍，0.96倍，1.50倍和0.91倍。对于上述代谢物，代谢产物与口服母体化合物的AUC比率是母体药物的AUC的3.66倍，9.19倍，12.97倍和9.92倍，分别。AL-total（AL，AL-GSH，AL-Cys）和IAL-total（IAL，IAL-GSH，IAL-Cys）的生物利用度分别为8.39％和13.07％，分别是3.62和6.95倍分别为AL（2.32％）和IAL（1.88％）。如果仅对母体药物进行测试，则口服接触量将被低估。这些发现为临床前安全性评估以及预测人类的AL和IAL代谢提供了有用的信息。