轉(zhuǎn)運(yùn)蛋白（OAT和OATP）有助于說(shuō)明元胡止痛處方中不同性質(zhì)成分的藥物相容性機(jī)理
Acta Pharmaceutica Sinica B ( IF 11.413 ) Pub Date : 2020-06-27 , DOI:

根據(jù)中藥相容性理論，結(jié)合不同口味的多種藥用成分，達(dá)到較好的療效，但機(jī)理尚不十分清楚。在這里，作者研究了成分與人類轉(zhuǎn)運(yùn)蛋白（例如腎臟轉(zhuǎn)運(yùn)蛋白OAT1和OAT3，肝臟轉(zhuǎn)運(yùn)蛋白OATP1B1和OATP1B3和腸轉(zhuǎn)運(yùn)蛋白OATP2B1）之間的相互作用，以識(shí)別元胡止痛制劑（YHP）中不同口味成分的相容性機(jī)理。包括延胡索（CYH）和當(dāng)歸（AD），可以通過(guò)限制中央系統(tǒng)來(lái)緩解疼痛。結(jié)果表明，CYH的主要成分四氫帕馬?。═DE）可以被OAT3轉(zhuǎn)運(yùn)到腎臟，OATP1B1和OATP1B3轉(zhuǎn)運(yùn)到肝臟，而歐前胡素（IPT）和異歐前胡素（ISP）是AD的兩個(gè)關(guān)鍵成分，并且是AD提取物對(duì)OAT1和OAT3表現(xiàn)出強(qiáng)烈的抑制作用。此外，AD提取物還對(duì)人類轉(zhuǎn)運(yùn)蛋白OATP1B1和OATP1B3產(chǎn)生了強(qiáng)烈的抑制作用。還檢測(cè)到IPT，ISP和AD提取物顯著下調(diào)了小鼠肝臟Oatp1a1，Oatp1a4和Oatp1b2的表達(dá)。在體內(nèi)結(jié)果表明，在存在IPT，ISP和AD提取物的情況下，肝臟和腎臟中TDE的濃度顯著降低，而血液和大腦中的TDE濃度均顯著提高。這些結(jié)果表明，具有刺激性味道的AD中的成分可以通過(guò)抑制肝和腎中TDE的攝取來(lái)增加血液和腦中TDE的暴露。也就是說(shuō)，具有苦味的TDE可能會(huì)“泛濫”到中樞神經(jīng)系統(tǒng)中，從而在AD中存在成分的情況下將其切斷為肝和腎，從而發(fā)揮其治療作用。本文不僅通過(guò)OAT3，OATP1B1和OATP1B3的作用證明了CYH在肝臟和腎臟中的子午線分布，而且還闡明了如何通過(guò)合理地與AD相容來(lái)提高CYH的療效。

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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