基于“物质-药代-功效”关联研究桑叶解热质量标志物成药性

Druggability Study of Antipyretic Quality Maker in Mulberry Leaf Based on the Correlation of“Substance-Pharmacokinetics-Effects”

目的阐释桑叶解热质量标志物(色氨酸)量效关系、作用机制及体内暴露情况等关键质量属性,基于“物质-药代-功效”关联展开桑叶解热质量标志物成药性研究。方法以酵母致大鼠发热模型为研究对象,评价色氨酸与其他成分的协同作用,并进行量效关系研究;采用ELISA法对色氨酸干预后大鼠下丘脑进行检测,解析色氨酸解热作用机制;通过UPLC-QQQ-MS技术测定色氨酸的药代动力学行为。结果与同浓度色氨酸组相比,桑叶超载色氨酸组解热效果没有明显提升;不同浓度色氨酸组中,色氨酸1倍剂量组解热效果明显,解热机制可能与色氨酸抑制下丘脑内体温调节因子PGE2的生成有关。灌胃同剂量色氨酸后,模型组和空白组半小时后血药浓度均达峰值,模型组大鼠的AUC和C_(max)显著大于空白组,模型组平均驻留时间大于空白组。结论与对乙酰氨基酚相比,色氨酸对持续性高热效果更为显著,药动学行为与发热病理状态具有相关性,在发热大鼠体内暴露量增加,生物利用度提高,为其后续新药高质量研发提供有益参考,也为“物质-药代-功效”关联的中药创新研发思路提供实验依据。

Objective To elucidate the dose-effect relationship,mechanism of action,exposure and other key quality attributes of anti-pyretic quality markers(tryptophan)of mulberry leaves,and to investigated the druggability of antipyretic quality markers of mulberry leaves based on the correlation of“substance-pharmacokinetic-efficacy”.Methods The yeast induced fever model of rats was taken as the research object to evaluate the synergistic effect of tryptophan and other components,and the dose-effect relationship was studied.The hypothalamus of rats after the intervention of tryptophan were detected by ELISA,and the anti-pyretic mechanism of tryptophan was analyzed.Pharmacokinetic behavior of tryptophan was determined by using the UPLC-QQQ-MS technology.Results Compared with the same concentration of tryptophan group,the antipyretic effect of mulberry leaf overload group was not significantly improved.In different concentrations of tryptophan,the anti-pyretic effect was obvious in the one-dose tryptophan group.The anti-pyretic mechanism may be related to the inhibition of tryptophan on the production of thermoregulatory factor PGE2 in the hypothalamus.After gavage with the same dose of tryptophan,the blood concentration of model group and blank group reached the peak half an hour later.The AUC and C_(max)of model group were significantly higher than that of blank group,and the average dwell time of model group was higher than that of blank group.Conclusion Compared with acetaminophen,the effect of tryptophan on persistent high fever is more significant.The pharmacokinetic behavior is correlated with the pathological state of fever,and the exposure in the body of fever rats is increased,and the bioavailability is improved,which provides a useful reference for the high-quality research and development of new drugs.It also provides experimental basis for the innovative research and development of traditional Chinese medicine related with"substance-pharmacokinetics-efficacy".