Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

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

doi:10.1016/j.apsb.2020.05.012

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

Acta Pharm Sin B. 2020 Sep;10(9):1646-1657. doi: 10.1016/j.apsb.2020.05.012. Epub 2020 Jun 27.

Authors

Ze Wang^{1

2}, Haihua Shang^{3

4}, Yazhuo Li², Chen Zhang^{2

5}, Yan Dong⁶, Tao Cui^{1

2}, Hongbing Zhang², Xiaoyan Ci², Xiulin Yi², Tiejun Zhang², Fengying Yan², Yaping Zhang⁷, Xing Huang⁸, Weidang Wu², Changxiao Liu^{1

2

3}

Affiliations

¹ Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
² Biotechnology Center, Tianjin Institute of Pharmaceutical Research Co. Ltd., Tianjin 300193, China.
³ Tianjin Institute of Pharmaceutical Research New Drug Evaluation Research Co. Ltd., State Key Laboratory of Drug Release Technology and Pharmacokinetics, Tianjin 300031, China.
⁴ Shenyang Pharmaceutical University, Shenyang 110016, China.
⁵ Anhui Medical University, Hefei 230032, China.
⁶ Chu Hsien-I Memorial Hospital, Tianjin Medical University, Tianjin 300134, China.
⁷ Emergency Department, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁸ Hefei Tianhui Hatching Technology Co. Ltd., Hefei 230032, China.

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.

Keywords: Drug–drug interaction; OAT1; OAT3; OATP1B1; OATP1B3; OATP2B1; Transporters; Yuanhuzhitong prescription.