Dose proportionality studies of novel thiazolidinedione derivatives as potent antidiabetic agents in mice

The determination of the plasma concentrations of the new oral antidiabetic agents BM 13.1246 ((+/-)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] benzyl]-2,4-thiazolidinedione), [sequence: see text] BM 13.1215 ((+/-)-5-[(5-methyl-2-phenyl-4-oxazolyl)-methyl-2- benzofuranyl-5-methyl]-2,4-oxazolidinedione), [sequence: see text] and BM 50.1050 ((+/-)-5[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] naphthalyl]methyl-2,4-thiazolidinedione) [sequence: see text] in ob/ob mice plasma was performed by using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet (270 nm) detection. The analytical procedures have recoveries of more than 80%, and a between-run precision of less than 4% for all analysed compounds. The pharmacokinetic behaviour, especially the dose proportionality, was investigated in ob/ob mice after repeated oral doses of 1 and 10 mg/kg, respectively. All compounds were absorbed quickly and attained maximum plasma concentrations within 2-5 h after administration. In the examined interval of dosing, an approximately proportional increase of the plasma levels for BM 13.1246 and BM 50.1050 was observed. After repeated oral doses the terminal half-lives are about 4 h for BM 13.1246, 8 h for BM 13.1215, and 6 h for BM 50.1050.