title: Antitumor activity of caffeic acid 3,4-dihydroxyphenethyl ester and its pharmacokinetic and metabolic properties.
abstract: 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.
authors: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Xin
authors: X
authors: Guo
authors: Lu
authors: L
authors: Shen
authors: Yuhua
authors: Y
authors: Tong
authors: Jian
authors: J
authors: Zhang
authors: Gang
authors: G
authors: Wu
authors: Qiong
authors: Q
authors: He
authors: Siran
authors: S
authors: Yu
authors: Xuewei
authors: X
authors: Ye
authors: Libo
authors: L
authors: Zou
authors: Zhizhen
authors: Z
authors: Zhang
authors: Xiao-Yuan
authors: XY
authors: Lian
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000378:metabolism; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D002109:Caffeic Acids; C548196:caffeic acid 3,4-dihydroxyphenethyl ester; C005975:3,4-dihydroxyphenylethanol; D010626:Phenylethyl Alcohol
keywords: Antitumor; HPLC; Hydroxyphenethylester of caffeic acid; LC/MS; Metabolites; Pharmacokinetics