In vitro cytotoxicity, pharmacokinetics and tissue distribution in rats of MXN-004, a novel conjugate of polyethylene glycol and SN38. (June 2014)

• Record Type: Journal Article
• Authors: Zhou, Sufeng; Li, Ning; Wang, Xin; Li, Cuiyun; Tian, Fengjie; Ren, Shuangxia; Zhang, Yuehua; He, Yuanping; Qiu, Zhixia; Zhao, Di; Chen, Xijing
• Is Part Of: Xenobiotica. Volume 44:Number 6(2014:Jun.)
• Page Start: 562
• Page End: 569
• Publication Date: 2014-06
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.868061
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. <?ri?>MXN-004 is a water-soluble PEGylated 7-ethyl-10-hydroxy-camptothecin (SN38). The aim of this study was to evaluate the <italic>in vitro</italic> cytotoxicity of MXN-004 and investigate pharmacokinetics and tissue distribution of MXN-004 and its active metabolite SN38 in rats.</p> <p>2. <?ri?><italic>In vitro</italic> cytotoxicity of MXN-004 was tested in A549, HepG2 and Caco-2 cancer cell lines by a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and compared with irinotecan. The pharmacokinetics and tissue distribution of MXN-004, irinotecan and their identical active metabolite SN38 were investigated after intravenous administration of MXN-004 and irinotecan at a same dose level of 16 μmol/kg in rats.</p> <p>3. <?ri?><italic>In vitro</italic> cytotoxicity study showed that MXN-004 was more potent in comparison with irinotecan. In rats, MXN-004 exhibited a longer half-life (sixfold) and much greater <italic>V</italic><sub>ss</sub> as compared with irinotecan. The AUC<sub>0–∞</sub>, <italic>T</italic><sub>1/2</sub> and <italic>C</italic><sub>max</sub> of SN38 after intravenous administration of MXN-004 were higher than those of irinotecan (3.5-, 1.92- and 10.6-fold, respectively). In addition, the concentrations of SN38 released from MXN-004 were significantly higher in all tissues than those from irinotecan, especially in the lung.</p> <p>4. <?ri?>These results suggested that MXN-004 might be a more potential water-soluble antitumor agent with prolonged half-life of SN38 compared to irinotecan.</p> </abstract>