School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People's Republic of China.
Drug Des Devel Ther. 2022 Dec 23;16:4365-4383. doi: 10.2147/DDDT.S385301. eCollection 2022.
Berberine (BBR) is the primary active component of Phellodendri Chinensis Cortex (PCC), which has been traditionally used to treat inflammatory diseases. However, the discrepancy between its low bioavailability and significant therapeutic effect remains obscure. The purpose of this study was to explore the previously unsolved enigma of the low bioavailability of BBR and its appreciable anti-inflammatory effect to reveal the action mechanism of BBR and PCC.
The quantitative analysis of BBR and its metabolite oxyberberine (OBB) in blood and tissues was performed using high-performance liquid chromatography to investigate the conversion and distribution of BBR/OBB mediated by erythrocytes. Routine blood tests and immunohistochemical staining were used to explore the potential relationship between the amounts of monocyte/macrophage and the drug concentration in erythrocytes and tissues (liver, heart, spleen, lung, kidney, intestine, muscle, brain and pancreas). To comparatively explore the anti-inflammatory effects of BBR and OBB, the acetic acid-induced vascular permeability mice model and lipopolysaccharide-induced RAW 264.7 macrophages were employed.
Nearly 92% of BBR existed in the erythrocytes in rats. The partition coefficient of BBR between plasma and erythrocytes (Kp/b) decreased with time. OBB was found to be the oxidative metabolite of BBR in erythrocytes. Proportion of BBR/OBB in erythrocytes changed from 9.38% to 16.30% and from 13.50% to 46.24%, respectively. There was a significant relationship between the BBR/OBB concentration in blood and monocyte depletion after a single administration of BBR. BBR/OBB was transported via erythrocytes to various tissues (liver, kidney, spleen, lung, and heart, etc), with the liver achieving the highest concentration. OBB exhibited similar anti-inflammatory effect in vitro and in vivo as BBR with much smaller dosage.
BBR was prodominantly found in erythrocytes, which was critically participated in the biodistribution, pharmacokinetics, metabolism and target delivery of BBR and its metabolite. The anti-inflammatory activity of BBR and PCC was intimately associated with the metabolism into the active congener OBB and the targeted delivery to monocytes/macrophages mediated by the erythrocytes.
小檗碱（BBR）是黄柏（Phellodendri Chinensis Cortex，PCC）的主要活性成分，传统上用于治疗炎症性疾病。然而，其生物利用度低与显著治疗效果之间的差异仍不清楚。本研究旨在探讨 BBR 生物利用度低及其显著抗炎作用这一未解之谜，以揭示 BBR 和 PCC 的作用机制。
采用高效液相色谱法对血液和组织中的 BBR 及其代谢物氧化小檗碱（OBB）进行定量分析，研究红细胞介导的 BBR/OBB 转化和分布。常规血液检查和免疫组织化学染色用于探讨红细胞和组织（肝、心、脾、肺、肾、肠、肌肉、脑和胰腺）中单核细胞/巨噬细胞数量与药物浓度之间的潜在关系。为了比较 BBR 和 OBB 的抗炎作用，采用醋酸诱导的血管通透性小鼠模型和脂多糖诱导的 RAW 264.7 巨噬细胞。
在大鼠体内，近 92%的 BBR 存在于红细胞中。BBR 在血浆和红细胞之间的分配系数（Kp/b）随时间降低。在红细胞中发现 BBR 的氧化代谢物为 OBB。红细胞中 BBR/OBB 的比例分别从 9.38%变为 16.30%和从 13.50%变为 46.24%。单次给予 BBR 后，血液中 BBR/OBB 浓度与单核细胞耗竭之间存在显著关系。BBR/OBB 通过红细胞转运至各种组织（肝、肾、脾、肺和心脏等），其中肝脏的浓度最高。OBB 在体外和体内均表现出与 BBR 相似的抗炎作用，但其剂量要小得多。
BBR 主要存在于红细胞中，这对于 BBR 及其代谢物的生物分布、药代动力学、代谢和靶向递送具有重要意义。BBR 和 PCC 的抗炎活性与代谢为活性同系物 OBB 以及红细胞介导的向单核细胞/巨噬细胞的靶向递送密切相关。
