Simultaneous determination of the novel thiosemicarbazone anti-cancer agent, Bp4eT, and its main phase I metabolites in plasma: Application to a pilot pharmacokinetic study in rats

Autor: Jaroslav Roh, Petra Kovaříková, Danuta S. Kalinowski, Ján Stariat, Vit Sestak, Tomáš Eisner, Des R. Richardson, Jiří Klimeš, Milan Nobilis, Přemysl Mladěnka, Tomáš Šimůnek, Vlasta Suprunová, Tomáš Filipský
Rok vydání: 2013
Předmět:
Zdroj: Biomedical Chromatography. 28:621-629
ISSN: 0269-3879
DOI: 10.1002/bmc.3080
Popis: Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 μM for Bp4eT, 0.02-0.37 μM for both M1-E and M1-Z, and 0.10-1.60 μM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. Copyright © 2013 John Wiley & Sons, Ltd. Additional supporting information may be found in the online version of this article at the publisher's web site.
Databáze: OpenAIRE
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