转运蛋白（OAT和OATP）有助于说明元胡止痛处方中不同性质成分的药物相容性机理
Acta Pharmaceutica Sinica B ( IF 11.413 ) Pub Date : 2020-06-27 , DOI:
根据中药相容性理论，结合不同口味的多种药用成分，达到较好的疗效，但机理尚不十分清楚。在这里，作者研究了成分与人类转运蛋白（例如肾脏转运蛋白OAT1和OAT3，肝脏转运蛋白OATP1B1和OATP1B3和肠转运蛋白OATP2B1）之间的相互作用，以识别元胡止痛制剂（YHP）中不同口味成分的相容性机理。包括延胡索（CYH）和当归（AD），可以通过限制中央系统来缓解疼痛。结果表明，CYH的主要成分四氢帕马汀（TDE）可以被OAT3转运到肾脏，OATP1B1和OATP1B3转运到肝脏，而欧前胡素（IPT）和异欧前胡素（ISP）是AD的两个关键成分，并且是AD提取物对OAT1和OAT3表现出强烈的抑制作用。此外，AD提取物还对人类转运蛋白OATP1B1和OATP1B3产生了强烈的抑制作用。还检测到IPT，ISP和AD提取物显着下调了小鼠肝脏Oatp1a1，Oatp1a4和Oatp1b2的表达。在体内结果表明，在存在IPT，ISP和AD提取物的情况下，肝脏和肾脏中TDE的浓度显着降低，而血液和大脑中的TDE浓度均显着提高。这些结果表明，具有刺激性味道的AD中的成分可以通过抑制肝和肾中TDE的摄取来增加血液和脑中TDE的暴露。也就是说，具有苦味的TDE可能会“泛滥”到中枢神经系统中，从而在AD中存在成分的情况下将其切断为肝和肾，从而发挥其治疗作用。本文不仅通过OAT3，OATP1B1和OATP1B3的作用证明了CYH在肝脏和肾脏中的子午线分布，而且还阐明了如何通过合理地与AD相容来提高CYH的疗效。
Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in Yuanhuzhitong prescription
Acta Pharmaceutica Sinica B ( IF 11.413 ) Pub Date : 2020-06-27 , DOI: 10.1016/j.apsb.2020.05.012
Ze Wang , Haihua Shang , Yazhuo Li , Chen Zhang , Yan Dong , Tao Cui , Hongbing Zhang , Xiaoyan Ci , Xiulin Yi , Tiejun Zhang , Fengying Yan , Yaping Zhang , Xing Huang , Weidang Wu , Changxiao Liu
Abstract:
Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy, while the mechanism was not very clear. Here, the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3, the liver transporters OATP1B1 and OATP1B3, and the intestine transporter OATP2B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation (YHP) comprising Corydalis yanhusuo (CYH) and Angelica dahurica (AD), which could relieve pain by restraining the central system. The results show that tetrahydropalmatine (TDE), the major component of CYH, could be transported by OAT3 into kidney, OATP1B1 and OATP1B3 into liver, while imperatorin (IPT) and isoimperatorin (ISP), the two key components of AD, and AD extract showed strong inhibition to OAT1 and OAT3. What’s more, AD extract also exerted strongly inhibition to human transporters OATP1B1 and OATP1B3. It was also detected that IPT, ISP, and AD extract significantly downregulated the expression of Oatp1a1, Oatp1a4, and Oatp1b2 of liver in mice. The in vivo results show that the concentration of TDE in liver and kidney significantly decreased, while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT, ISP, and AD extract. These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney. That is to say, TDE with bitter taste could “flood up” into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD. This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3, OATP1B1, and OATP1B3, but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD. This study may offer a valuable clue to illustrate the mechanism of compatibility theory.
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