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Casiopeina III-Ea is a mixed chelate copper (II) complex that has shown cytotoxic and antitumor activity in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of total copper derived from casiopeina III-Ea administered by intravenous bolus injection to Wistar rats. Other objective was to evaluate the hematotoxicity produced by this compound in those animals. Wistar rats received a single intravenous dose of 4 mg/kg of casiopeina III-Ea. Blood samples were taken and pharmacokinetics evaluated. Furthermore, erythrocyte copper levels were determined to identify a potential target and Zn levels were analyzed to determine a possible change. For the evaluation of hematotoxicity, both blood and urine samples were collected for hematological and biochemical analyses; moreover, Fe determination was performed. Blood copper and zinc levels, red blood cell copper levels as well as copper, zinc, and iron amounts excreted into urine were analyzed by ICP-MS. The blood concentration-time profile of copper derived from casiopeina III-Ea was fitted to a two-compartment model with a zero-order input. Cumulative amounts of Cu, Zn, and Fe excreted into rat urine after administration of casiopeina III-Ea were different with respect to control. Hematological and biochemical data indicated a hemolytic toxicity. Pharmacokinetic analysis of total copper derived from casiopeina III-Ea provided a general knowledge about distribution and elimination process of this compound. Additionally, the systemic exposure of the copper derived from casiopeina III-Ea accounts for the hematotoxicity of this complex at test dose., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

We present herein the results of a pharmacokinetic (PK) study of CuII mixed-chelate coordination compound CasIII-La {[Cu(5,6-dimethyl-1,10-phenanthroline)(acetylacetonate)(H2O)]NO3}, which belongs to the antineoplastic family of compounds known as Casiopeínas. The main interest in this molecule lies in the big difference in its lethal dose and PK parameters in Wistar rats compared with its structural isomer CasIII-Ea {[Cu(4,7-dimethyl-1,10-phenanthroline)(acetylacetonate)(H2O)]NO3}. For instance, the half-lives of these compounds are 9.6 ± 1.15 and 48 ± 4.6 h for CasIII-La and CasIII-Ea, respectively. The differences in the half-lives have been attributed to their different capacities to cross cellular membranes. Molecular dynamics studies of a fraction of a cell membrane and Casiopeínas were developed to identify the possible intermolecular interactions responsible for the retention of the compound inside the cellular membrane. Also, quantum theory of atoms-in-molecules studies was developed to determine the capacity of the hydrogen atoms of methyl groups to participate in intermolecular interactions. In addition, peripheral human blood lymphocyte and macrophage samples were used to determine the cross-membrane effect on cytotoxicity. [ABSTRACT FROM AUTHOR]