title: 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.
abstract: 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.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Stariat
authors.forename: Vlasta
authors.initials: V
authors.lastname: Suprunová
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Roh
authors.forename: Vít
authors.initials: V
authors.lastname: Šesták
authors.forename: Tomáš
authors.initials: T
authors.lastname: Eisner
authors.forename: Tomáš
authors.initials: T
authors.lastname: Filipský
authors.forename: Přemysl
authors.initials: P
authors.lastname: Mladěnka
authors.forename: Milan
authors.initials: M
authors.lastname: Nobilis
authors.forename: Tomáš
authors.initials: T
authors.lastname: Šimůnek
authors.forename: Jiří
authors.initials: J
authors.lastname: Klimeš
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Petra
authors.initials: P
authors.lastname: Kovaříková
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D008297:Male; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013882:Thiosemicarbazones / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: C550921:2-benzoylpyridine 4-ethyl-3-thiosemicarbazone; D000970:Antineoplastic Agents; D013882:Thiosemicarbazones
keywords: 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone; Bp4eT; LC-MS; anti-cancer; pharmacokinetics