Pharmacological and pharmacokinetic studies of anti-diabetic tropolonato-Zn(II) complexes with Zn(S2O2) coordination mode

Abstract

Zn(II) complexes are expected to be useful in the treatment of diabetes mellitus because of the hypoglycemic effect produced by its insulin-mimetic activity. Previous reports indicated that Zn(II) complexes with coordinating sulfur exhibit higher insulin-mimetic activity. In this study, we investigated the pharmacological and pharmacokinetic differences between Zn(O4) and Zn(S2O2) coordination modes of tropolonato-Zn(II) complexes with insulin-mimetic activity. Among the tropolonato-Zn(II) complexes with various coordination modes, di(2-mercaptotropolonato)zinc(II) (ZT2) with the Zn(S2O2) coordination mode was found to exhibit the highest in vitro insulin-mimetic activity with respect to inhibition of free fatty acid (FFA) release and enhancement of glucose uptake in isolated rat adipocytes treated with adrenaline. On comparing investigations of the antidiabetic effect in vivo, ZT2 was found to exhibit potent hypoglycemic activity and improve insulin resistance in type 2 diabetic KKAy mice at a low orally administered daily dose. Di(tropolonato)zinc(II) (ZT1), which has the Zn(O4) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the 65Zn tracer method, ZT2 was found to be absorbed at a significantly slower rate with a longer half-life than was ZT1. These results suggest that the potent hypoglycemic activity of ZT2 might be attributed to its long half-life. © 2012 The Pharmaceutical Society of Japan.