Wang Qun, Wang Yonglin, Liu Wen, Lu Dingyan, Jin Yang, Tang Nian, Shi Ya, Gong Zipeng, Tian Weiyi, Liu Ting
Guizhou University of Traditional Chinese Medicine, Huaxi University Town, Guiyang 550025, China.
Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Beijing Road, Guiyang 550004, China.
Evid Based Complement Alternat Med. 2022 Oct 15;2022:2481654. doi: 10.1155/2022/2481654. eCollection 2022.
The aim of this study was to explore the mechanisms underlying the differences in the pharmacokinetics of Huangqi Liuyi decoction extract (HQD) under physiological and pathological conditions. The roles of liver cytochrome P450 metabolic enzymes (Cyp450) and small intestinal transporters were also investigated. The cocktail probe drug method was used to investigate the effects of diabetic nephropathy (DN) and HQD on metabolic enzyme activity. The expression levels of liver Cyp450 metabolic enzymes (Cyp1A2, Cyp2C37, Cyp3A11, Cyp2E1, and Cyp2C11) and small intestinal transporters (breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporters (OCTs), and multidrug resistance-associated protein (MRPs) were determined using western blot. Compared to normal mice, the expression of OCT1, OCT2, MRP1, and MRP2 was increased in DN mice, while that of P-gp and BCRP ( < 0.05 and < 0.001) was inhibited. HQD inhibited expression of Cyp1A2 and Cyp3A11 and increased the expression of P-gp and BCRP in normal mice. In DN mice, HQD induced expression of BCRP and inhibited expression of Cyp2C37, Cyp3A11, OCT2, MRP1, and MRP2. The activity of each Cyp450 enzyme was consistent with changes in expression. The changes in pharmacokinetic parameters of HQD in DN might, in part, be secondary to decreased expression of P-gp and BCRP. HQD varied in regulating transporter activities between health and disease. These findings support careful application of HQD-based treatment in DN, especially in combination with other drugs.
本研究旨在探讨生理和病理条件下黄芪六一汤提取物（HQD）药代动力学差异的潜在机制。同时也研究了肝脏细胞色素P450代谢酶（Cyp450）和小肠转运体的作用。采用鸡尾酒探针药物法研究糖尿病肾病（DN）和HQD对代谢酶活性的影响。使用蛋白质免疫印迹法测定肝脏Cyp450代谢酶（Cyp1A2、Cyp2C37、Cyp3A11、Cyp2E1和Cyp2C11）和小肠转运体（乳腺癌耐药蛋白（BCRP）、P-糖蛋白（P-gp）、有机阳离子转运体（OCTs）和多药耐药相关蛋白（MRPs））的表达水平。与正常小鼠相比，DN小鼠中OCT1、OCT2、MRP1和MRP2的表达增加，而P-gp和BCRP的表达受到抑制（<0.05和<0.001）。HQD抑制正常小鼠中Cyp1A2和Cyp3A11的表达，并增加P-gp和BCRP的表达。在DN小鼠中，HQD诱导BCRP的表达，并抑制Cyp2C37、Cyp3A11、OCT2、MRP1和MRP2的表达。每种Cyp450酶的活性与表达变化一致。DN中HQD药代动力学参数的变化可能部分归因于P-gp和BCRP表达的降低。HQD在健康和疾病状态下调节转运体活性的作用有所不同。这些发现支持在DN中谨慎应用基于HQD的治疗方法，尤其是与其他药物联合使用时。
