Characterization and biotransformation in the plasma and red blood cells of VIVO2 + complexes formed by ceftriaxone

• The coordinating capability of third-generation cephalosporin ceftriaxone toward VIVO2 + is studied.
• The behavior in aqueous solution of VIVO2 + complexes of ceftriaxone and its models is examined.
• The interaction of VIVO2 +–ceftriaxone species with transferrin is described.
• The uptake and biotransformation inside the erythrocytes of VIVO2 +–ceftriaxone species are discussed.

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 VIVO2 + 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 VIVO2 + 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 VIVO2 + ion to cross the erythrocyte membrane. Inside the cell cis-[VO(Hcef)2(H2O)]2 − decomposes and the same species formed by inorganic VIVO2 + are observed. The relationship between the biotransformation in the plasma and red blood cells and the potential pharmacological activity of VIVO2 + species of ceftriaxone is finally discussed.

The formation of VIVO2 + complexes with third-generation cephalosporin ceftriaxone and with some model ligands was studied in aqueous solution. The interaction with transferrin at the physiological conditions and the uptake and biotransformation in the red blood cells were also discussed.Figure optionsDownload as PowerPoint slide