title: In vitro cytotoxicity, pharmacokinetics and tissue distribution in rats of MXN-004, a novel conjugate of polyethylene glycol and SN38.
abstract: 1.  MXN-004 is a water-soluble PEGylated 7-ethyl-10-hydroxy-camptothecin (SN38). The aim of this study was to evaluate the in vitro cytotoxicity of MXN-004 and investigate pharmacokinetics and tissue distribution of MXN-004 and its active metabolite SN38 in rats. 2.  In vitro 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. 3.  In vitro 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 Vss as compared with irinotecan. The AUC0-∞, T1/2 and Cmax 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. 4.  These results suggested that MXN-004 might be a more potential water-soluble antitumor agent with prolonged half-life of SN38 compared to irinotecan.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China and.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Li
authors.forename: Fengjie
authors.initials: F
authors.lastname: Tian
authors.forename: Shuangxia
authors.initials: S
authors.lastname: Ren
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuanping
authors.initials: Y
authors.lastname: He
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: C000593914:MXN-004; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin