Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat.
The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)(2)] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)(2)] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)(2)-related complexes by the blood circulation monitoring-electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC(50) (IC(50) is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P (com)). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)(2) than in the blood of rats that received VO(3hp)(2) or bis(kojato)oxovanadium(IV); VO(alx)(2) also exhibited higher log P (com) and 1/IC(50) values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.
Yasui
Hiroyuki
H
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. yasui@mb.kyoto-phu.ac.jp
Adachi
Yusuke
Y
Katoh
Akira
A
Sakurai
Hiromu
H
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D004578:Electron Spin Resonance Spectroscopy; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000097:blood* / Q000493:pharmacokinetics; D050356:Lipid Metabolism; D008297:Male; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014638:Vanadates / Q000097:blood* / Q000493:pharmacokinetics
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D014638:Vanadates