title: Enhanced lactone stability of CZ48 in blood correlates to its lack of toxicity in mice.
abstract: OBJECTIVE
  The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice.
  
  
  METHODS
  In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations.
  
  
  RESULTS
  The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules.
  
  
  CONCLUSIONS
  The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood.
authors.affiliation: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link Road, Houston, Texas 77025, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Cao
authors.forename: Max
authors.initials: M
authors.lastname: Zhan
authors.forename: Dana
authors.initials: D
authors.lastname: Vardeman
authors.forename: Beppino
authors.initials: B
authors.lastname: Giovanella
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005243:Feces / Q000737:chemistry; D005260:Female; D007783:Lactones / Q000097:blood; D051379:Mice; D008819:Mice, Nude
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; C532663:camptothecin, C20-propionate ester; D002166:Camptothecin