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Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat

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Abstract

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/IC50 (IC50 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/IC50 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.

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Acknowledgement

This study was supported by a Grant-in-Aid to H.S. from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government for Specially Promoted Research.

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Authors and Affiliations

  1. Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Hiroyuki Yasui, Yusuke Adachi & Hiromu Sakurai

  2. Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kitamachi, Kichijoji, Musashino-shi, Tokyo, 180-8633, Japan

    Akira Katoh

Authors
  1. Hiroyuki Yasui
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  2. Yusuke Adachi
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  3. Akira Katoh
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  4. Hiromu Sakurai
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Correspondence to Hiroyuki Yasui or Hiromu Sakurai.

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Yasui, H., Adachi, Y., Katoh, A. et al. Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat. J Biol Inorg Chem 12, 843–853 (2007). https://doi.org/10.1007/s00775-007-0239-5

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  • DOI: https://doi.org/10.1007/s00775-007-0239-5

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