A new halogenated antidiabetic vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV): in vitro and in vivo insulinomimetic evaluations and metallokinetic analysis.
A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)2, with a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic acid and VOSO4 at pH 5, with the structure characterized by electronic absorption, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50 = 0.45 mM) compared with that of bis(picolinato)oxovanadium(IV) (IC50 = 0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized when VO(IPA)2 was given by daily intraperitoneal injection. The normoglycemic effect continued for more than 14 days after the end of treatment. To understand the insulinomimetic action of VO(IPA)2, the organ distribution of vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)2, vanadium was distributed in almost all tissues examined, especially in bone, indicating that the action of vanadium is not peripheral. Vanadyl concentrations in the blood of normal rats given VO(IPA)2 remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)2 binds with the membrane of erythrocytes, probably owing to its high hydrophobicity in addition to its binding with serum albumin. The longer residence of vanadyl species shows the higher normoglyceric effects of VO(IPA)2 among three complexes with the VO(N2O2) coordination mode. On the basis of these results, VO(IPA)2 is indicated to be a preferred agent to treat insulin-dependent diabetes mellitus in experimental animals.
Takino
T
T
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Japan.
Yasui
H
H
Yoshitake
A
A
Hamajima
Y
Y
Matsushita
R
R
Takada
J
J
Sakurai
H
H
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001775:Blood Circulation; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007455:Iodine / Q000737:chemistry; D008024:Ligands; D008657:Metabolic Clearance Rate; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013057:Spectrum Analysis; D013311:Streptozocin; D014018:Tissue Distribution; D014638:Vanadates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D008024:Ligands; D009942:Organometallic Compounds; D010848:Picolinic Acids; C435299:bis(5-iodopicolinato)oxovanadium(IV); C095866:bis(picolinato)oxovanadium(IV); C075743:oxovanadium IV; D014638:Vanadates; D013311:Streptozocin; D007455:Iodine