Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Commun Biol. 2022 Aug 12;5(1):807. doi: 10.1038/s42003-022-03776-0.
Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compared to that of BBR, and BJ is more effective in treating obesity and its related metabolism in vitro and in vivo. We also find that BJ promotes mitochondrial biogenesis by inhibiting TBK1 and inducing AMP-activated protein kinase (AMPK) phosphorylation, and BJ increases adipocyte sensitivity to catecholamine by inhibiting IKKε. Together, our findings support that co-crystal BJ is likely to be an effective agent for treating obesity and its related metabolic diseases targeting TBK1 and IKKε.
小檗碱（BBR）对糖尿病、肥胖症和其他炎症相关疾病等多种疾病具有特定的治疗作用。然而，由于其溶解度和膜通透性差，小檗碱的口服生物利用度（低于 1%）较低，限制了其临床应用。在本文中，我们使用药物盐交换和共晶技术制备了 1:1 的小檗碱-布洛芬共晶（BJ）。药代动力学研究表明，BJ 的体内生物利用度是 BBR 的 3 倍，并且 BJ 在体外和体内治疗肥胖及其相关代谢方面更有效。我们还发现，BJ 通过抑制 TBK1 和诱导 AMP 激活蛋白激酶（AMPK）磷酸化来促进线粒体生物发生，并且 BJ 通过抑制 IKKε 来增加脂肪细胞对儿茶酚胺的敏感性。总之，我们的研究结果支持共晶 BJ 可能是一种有效的治疗肥胖及其相关代谢疾病的药物，其作用靶点是 TBK1 和 IKKε。
