College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Phytomedicine. 2013 Jul 15;20(10):904-12. doi: 10.1016/j.phymed.2013.04.002. Epub 2013 May 1.
Caffeic acid 3,4-dihydroxyphenethyl ester (CADPE), a natural polyphenol from Sarcandra glabra, has potent in vitro anticancer activity through multiple targets. This study investigated its in vivo anticancer efficacy and its pharmacokinetic and metabolic characteristics. CADPE at any of the dosage regimes (ip 2.5 mg/kg at an interval of 7 h, 12 h, or 24 h for eight days) significantly decreased tumor growth in hepatoma H22 and sarcoma S180 tumor-bearing mice. CADPE also significantly inhibited H22-induced acute ascites development. The in vivo anticancer efficacies of CADPE in these tumor models were equivalent to those of 5-fluorouracil (10 mg/kg, ip) and cyclophosphamide (10 mg/kg, ip), and CADPE did not show any toxicity. A high performance liquid chromatography method with the aid of liquid chromatography/mass spectrometry was established and validated for the pharmacokinetic and metabolic studies of CADPE. CADPE was detected in blood and the organs including liver, kidney, heart, spleen, and brain 1 min after tail intravenous administration, indicating that CADPE was able to quickly distribute to these organs. CADPE was quickly hydrolyzed both in mice and in vitro mice plasma, but was much stable in vitro human plasma, suggesting a better bioavailability of CADPE in human than in mice. The major metabolites of CADPE in mice were caffeic acid, hydroxytyrosol, and a CADPE glucuronide. This was the first time to reveal the pharmacokinetic and metabolic characteristics of CADPE. Taken together, CADPE had potent in vivo antitumor activity and was able to rapidly reach the body organs and to be hydrolyzed in blood to anticancer agents of caffeic acid and hydroxytyrosol. This study suggested that CADPE has the potential for the treatment of cancers and is worthy of further study.
咖啡酸 3,4-二羟基苯乙基酯（CADPE）是一种来自肿节风的天然多酚化合物，具有通过多种靶点发挥强大的体外抗癌活性。本研究探讨了其体内抗癌功效及其药代动力学和代谢特征。CADPE 在任何剂量方案（ip 2.5mg/kg，间隔 7、12 或 24 小时，连续 8 天）下均可显著抑制肝癌 H22 和肉瘤 S180 荷瘤小鼠的肿瘤生长。CADPE 还显著抑制 H22 诱导的急性腹水形成。CADPE 在这些肿瘤模型中的体内抗癌功效与 5-氟尿嘧啶（10mg/kg，ip）和环磷酰胺（10mg/kg，ip）相当，且 CADPE 无任何毒性。建立并验证了一种高效液相色谱法结合液质联用技术，用于 CADPE 的药代动力学和代谢研究。尾静脉给药后 1 分钟，即可在血液和包括肝、肾、心、脾和脑在内的器官中检测到 CADPE，表明 CADPE 能够迅速分布到这些器官。CADPE 在小鼠和小鼠血浆中均迅速水解，但在人血浆中则稳定得多，提示 CADPE 在人体内的生物利用度高于在小鼠中。CADPE 在小鼠中的主要代谢物为咖啡酸、羟基酪醇和 CADPE 葡萄糖醛酸苷。这是首次揭示 CADPE 的药代动力学和代谢特征。综上所述，CADPE 具有强大的体内抗肿瘤活性，能够迅速到达身体器官，并在血液中水解为咖啡酸和羟基酪醇等抗癌剂。本研究提示 CADPE 具有治疗癌症的潜力，值得进一步研究。
