Gong Zipeng, Yang Qing, Wang Yajie, Weng Xiaogang, Li Yujie, Dong Yu, Zhu Xiaoxin, Chen Ying
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2022 Jul 8;13:948678. doi: 10.3389/fphar.2022.948678. eCollection 2022.
The Wuji pill, also called Wuji Wan (WJW), is an effective traditional medicine for the clinical treatment of irritable bowel syndrome (IBS). It is principally composed of , , and . There have been no reports on the pharmacokinetics of WJW on IBS. Because it is more meaningful to study pharmacokinetics in relation to specific pathological conditions, our study investigated the pharmacokinetic differences of five representative components (berberine, palmatine, evodiamine, rutaecarpine, and paeoniflorin) in normal rats and chronic visceral hypersensitivity IBS (CVH-IBS) model rats after single dose and multiple doses of WJW using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Transmission electron microscopy, immunohistochemistry, and immunofluorescence were used to explore mechanisms behind the pharmacokinetic differences in terms of tight junction proteins (Occludin and ZO-1), myosin light chain kinase (MLCK), and transporters including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and multidrug resistance associated protein 2 (MRP2) in rat colons. After a single dose, for all components except rutaecarpine, significant differences were observed between normal and model groups. Compared with normal group, T and AUC of berberine and palmatine in model group increased significantly (562.5 ± 237.2 vs. 1,384.9 ± 712.4 min, 733.8 ± 67.4 vs. 1,532.4 ± 612.7 min; 5,443.0 ± 1,405.8 vs. 9,930.8 ± 2,304.5 min·ng/ml, 2,365.5 ± 410.6 vs. 3,527.0 ± 717.8 min·ng/ml), while Cl/F decreased (840.7 ± 250.8 vs. 397.3 ± 142.7 L/h/kg, 427.7 ± 89.4 vs. 288.9 ± 114.4 L/h/kg). C and AUC of evodiamine in model group increased significantly (1.4 ± 0.6 vs. 2.4 ± 0.7 ng/ml; 573 ± 45.3 vs. 733.9 ± 160.2 min·ng/ml), while T, T, Cl/F, and Vd/F had no significant difference. T and AUC of paeoniflorin in model group increased significantly (21.0 ± 8.2 vs. 80.0 ± 45.8 min; 15,428.9 ± 5,063.6 vs. 33,140.6 ± 5,613.9 min·ng/ml), while Cl/F decreased (110.5 ± 48.1 vs. 43.3 ± 9.5 L/h/kg). However, after multiple doses, all five components showed significant differences between normal and model groups. Moreover, these differences were related to tight junction damage and the differential expression of transporters in the colon, suggesting that dose adjustment might be required during administration of WJW in the clinical treatment of IBS.
无极丸，又称无极丸（WJW），是临床治疗肠易激综合征（IBS）的一种有效传统药物。它主要由[具体成分1]、[具体成分2]和[具体成分3]组成。目前尚无关于WJW治疗IBS的药代动力学报道。由于在特定病理条件下研究药代动力学更具意义，我们的研究采用超高效液相色谱串联质谱法（UPLC-MS/MS），研究了单剂量和多剂量WJW给药后，正常大鼠和慢性内脏高敏性IBS（CVH-IBS）模型大鼠体内五种代表性成分（小檗碱、巴马汀、吴茱萸碱、吴茱萸次碱和芍药苷）的药代动力学差异。采用透射电子显微镜、免疫组织化学和免疫荧光技术，从紧密连接蛋白（闭合蛋白和ZO-1）、肌球蛋白轻链激酶（MLCK）以及包括P-糖蛋白（P-gp）、多药耐药相关蛋白1（MRP1）和多药耐药相关蛋白2（MRP2）在内的转运体方面，探讨药代动力学差异背后的机制。单剂量给药后，除吴茱萸次碱外，所有成分在正常组和模型组之间均观察到显著差异。与正常组相比，模型组中小檗碱和巴马汀的T和AUC显著增加（562.5±237.2 vs. 1384.9±712.4分钟，733.8±67.4 vs. 1532.4±612.7分钟；5443.0±1405.8 vs. 9930.8±2304.5分钟·纳克/毫升，2365.5±410.6 vs. 3527.0±717.8分钟·纳克/毫升），而Cl/F降低（840.7±250.8 vs. 397.3±142.7升/小时/千克，427.7±89.4 vs. 288.9±114.4升/小时/千克）。模型组中吴茱萸碱的C和AUC显著增加（1.4±0.6 vs. 2.4±0.7纳克/毫升；573±45.3 vs. 733.9±160.2分钟·纳克/毫升），而T、T、Cl/F和Vd/F无显著差异。模型组中芍药苷的T和AUC显著增加（21.0±8.2 vs. 80.0±45.8分钟；15428.9±5063.6 vs. 33140.6±5613.9分钟·纳克/毫升），而Cl/F降低（110.5±48.1 vs. 43.3±9.5升/小时/千克）。然而，多剂量给药后，所有五种成分在正常组和模型组之间均显示出显著差异。此外，这些差异与结肠紧密连接损伤和转运体的差异表达有关，提示在IBS临床治疗中使用WJW时可能需要调整剂量。
