A new halogenated antidiabetic vanadyl complex bis(5-iodopicalinato)oxovanadium(IV): in vitro and in vivo insulinomimetic evaluations and metallokinetic analysis

A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)(2), wi th a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic aci d and VOSO4 at pH 5, with the structure characterized by electronic absorpt ion, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50=0.45 mM) compared wit h that of bis(picolinato)oxovanadium(IV) (IC50=0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized wh en VO(IPA)(2) was given by daily intraperitoneal injection. The normoglycem ic effect continued for more than 14 days after the end of treatment. To un derstand the insulinomimetic action of VO(IPA)(2), the organ distribution o f vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)(2), vanadium was distributed in almos t all tissues examined, especially in bone, indicating that the action of v anadium is not peripheral. Vanadyl concentrations in the blood of normal ra ts given VO(IPA)(2) remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)(2) binds wit h the membrane of erythrocytes, probably owing to its high hydrophobicity i n addition to its binding with serum albumin. The longer residence of vanad yl species shows the higher normoglyceric effects of VO(IPA)(2) among three complexes with the VO(N2O2) coordination mode. On the basis of these resul ts, VO(IPA)(2) is indicated to be a preferred agent to treat insulin-depend ent diabetes mellitus in experimental animals.