title: Characterization and biotransformation in the plasma and red blood cells of V(IV)O(2+) complexes formed by ceftriaxone.
abstract: The coordination mode and geometry in aqueous solution of oxidovanadium(IV) complexes formed by a third-generation cephalosporin, ceftriaxone (H3cef), were studied by spectroscopic (EPR, electron paramagnetic resonance), pH-potentiometric and computational (DFT, density functional theory) methods. The behavior of the model systems containing 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one (H2hmtdt) and 3-benzylthio-6-hydroxy-2-methyl-1,2,4-triazine-5(2H)-one (Hbhmt) was examined for comparison. The stability of the tautomers of ceftriaxone and 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one in the neutral, mono- and bi-anionic form was calculated by DFT methods, both in the gas phase and in aqueous solution, and the electron density on the oxygen atoms of the hydroxytriazinone ring was related to the pKa of the ligands. The data demonstrate that ceftriaxone coordinates V(IV)O(2+) forming mono- and bis-chelated complexes with (Oket, O(-)) donor set and formation of five-membered chelate rings. The geometry of the bis-chelated complex, cis-[VO(Hcef)2(H2O)](2-), is cis-octahedral and this species can deprotonate, around physiological pH, to form the corresponding mono-hydroxido cis-[VO(Hcef)2(OH)](3-). The interaction of cis-[VO(Hcef)2(H2O)](2-) with apo-transferrin (apo-hTf) was studied and the results suggest that V(IV)O(2+) distributes between (VO)apo-hTf/(VO)2apo-hTf and cis-[VO(Hcef)2(H2O)](2-), whereas mixed complexes are not formed for charge and steric effects. The interaction of cis-[VO(Hcef)2(H2O)](2-) with red blood cells shows that ceftriaxone helps V(IV)O(2+) ion to cross the erythrocyte membrane. Inside the cell cis-[VO(Hcef)2(H2O)](2-) decomposes and the same species formed by inorganic V(IV)O(2+) are observed. The relationship between the biotransformation in the plasma and red blood cells and the potential pharmacological activity of V(IV)O(2+) species of ceftriaxone is finally discussed.
authors.affiliation: Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07040 Sassari, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Sanna
authors.affiliation: Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07040 Sassari, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Fabbri
authors.affiliation: Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07040 Sassari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Serra
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, P.O. Box 21, H-4010 Debrecen, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Buglyó
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, P.O. Box 21, H-4010 Debrecen, Hungary.
authors.forename: Linda
authors.initials: L
authors.lastname: Bíró
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ugone
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy; Centro Interdisciplinare per lo Sviluppo della Ricerca Biotecnologica e per lo Studio della Biodiversità della Sardegna, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Micera
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy; Centro Interdisciplinare per lo Sviluppo della Ricerca Biotecnologica e per lo Studio della Biodiversità della Sardegna, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. Electronic address: garribba@uniss.it.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Garribba
mesh_terms: D002443:Ceftriaxone / Q000737:chemistry*; D056831:Coordination Complexes / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry; D008658:Inactivation, Metabolic; D010087:Oxides / Q000737:chemistry*; D011485:Protein Binding; D014168:Transferrin / Q000378:metabolism; D017968:Vanadium Compounds / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D007004:Hypoglycemic Agents; D010087:Oxides; D014168:Transferrin; D017968:Vanadium Compounds; C581824:vanadium dioxide; D002443:Ceftriaxone
keywords: Blood; Ceftriaxone; Density functional theory calculations; EPR spectroscopy; Vanadium