Shi Baimei, Yang Lingjian, Gao Tian, Ma Cuicui, Li Qiannan, Nan Yefei, Wang Shixiang, Xiao Chaoni, Jia Pu, Zheng Xiaohui
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University 195# Mail Box, No. 229 Northern Taibai Road Xi'an 710069 P. R. China
RSC Adv. 2019 Jan 30;9(7):4015-4027. doi: 10.1039/c8ra07972b. eCollection 2019 Jan 25.
Bornyl caffeate was initially discovered as a bioactive compound in medicinal plants. Despite the promising pharmacological activities including anti-tumor and antibacterial activities, the pharmacokinetics of the compound remain open. This work developed a high performance liquid chromatography-tandem mass spectrometric method for the determination of bornyl caffeate and caffeic acid (major metabolite and a main unit of bornyl caffeate) . Successful application of the method included identification of its metabolites and investigation on the drug pharmacokinetics. A total of 30 compounds were identified as the metabolites of bornyl caffeate in rats. We attributed these metabolites to phase I metabolic routes of reduction, oxidation, hydrolysis and phase II metabolic reactions of glucuronidation, sulfation, -methylation and glycine. Glucuronidation, sulfation, -methylation and reduction were the main metabolic pathways of bornyl caffeate. The method presented a linear range of 1-4000 ng mL. The pharmacokinetic profile of bornyl caffeate was found to be a three compartment open model, while caffeic acid fitted to a two compartment open model when it was administered alone or served as the main metabolite of bornyl caffeate. The time to peak concentration ( ) and the maximum plasma concentration ( ) of bornyl caffeate were 0.53 h and 409.33 ng mL. Compared with original caffeic acid, the compound displayed an increased half-life of elimination ( ), area under the concentration time curve from 0 to (AUC ) and area under the concentration time curve from 0 to ∞ (AUC), a decreased half-life of absorption ( ) and an identical . Taking together, we concluded that bornyl caffeate is able to rapidly initiate therapeutic effect and last for a relatively long time in rats; metabolic pathways of -methylation and reduction is key to interpret the mechanism and toxicity of bornyl caffeate.
咖啡酸龙脑酯最初是作为药用植物中的一种生物活性化合物被发现的。尽管其具有包括抗肿瘤和抗菌活性在内的良好药理活性，但该化合物的药代动力学仍不明确。本研究建立了一种高效液相色谱 - 串联质谱法，用于测定咖啡酸龙脑酯和咖啡酸（主要代谢产物及咖啡酸龙脑酯的主要结构单元）。该方法的成功应用包括其代谢产物的鉴定以及药物药代动力学研究。共鉴定出30种化合物为大鼠体内咖啡酸龙脑酯的代谢产物。我们将这些代谢产物归因于I相代谢途径中的还原、氧化、水解反应以及II相代谢反应中的葡萄糖醛酸化、硫酸化、N - 甲基化和甘氨酸化反应。葡萄糖醛酸化、硫酸化、N - 甲基化和还原反应是咖啡酸龙脑酯的主要代谢途径。该方法的线性范围为1 - 4000 ng/mL。发现咖啡酸龙脑酯的药代动力学特征符合三室开放模型，而咖啡酸单独给药或作为咖啡酸龙脑酯的主要代谢产物时符合二室开放模型。咖啡酸龙脑酯的达峰时间（tmax）和最大血浆浓度（Cmax）分别为0.53 h和409.33 ng/mL。与原咖啡酸相比，该化合物的消除半衰期（t1/2β）、0至tmax的浓度 - 时间曲线下面积（AUC0 - t）和0至∞的浓度 - 时间曲线下面积（AUC）增加，吸收半衰期（t1/2α）降低，而tmax相同。综上所述，我们得出结论：咖啡酸龙脑酯在大鼠体内能够迅速发挥治疗作用并持续较长时间；N - 甲基化和还原代谢途径是解释咖啡酸龙脑酯作用机制和毒性的关键。
