title: Pharmacological and pharmacokinetic studies of anti-diabetic tropolonato-Zn(II) complexes with Zn(S(2)O(2)) 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(O(4)) and Zn(S(2)O(2)) 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(S(2)O(2)) 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 KKA(y) mice at a low orally administered daily dose. Di(tropolonato)zinc(II) (ZT1), which has the Zn(O(4)) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the (65)Zn 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.
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Division of Analytical & Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Kyoto 607-8414, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Murakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D015032:Zinc / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D056831:Coordination Complexes; D007004:Hypoglycemic Agents; D007328:Insulin; D015032:Zinc