STUDIES ON THE METABOLISM OF THE NEW ANTIDIABETIC AGENT PIOGLITAZONE - IDENTIFICATION OF METABOLITES IN RATS AND DOGS

Metabolic studies of pioglitazone (CAS 105355-27-9, AD-4833), a new an tidiabetic agent, in rats and dogs using liquid chromatography/tandem mass spectrometry and H-1-nuclear magnetic resonance led to characteri zation of the following metabolites: the parent compound, (+/-)-5-(p-h ydroxybenzyl)-2,4-thiazolidinedione (M-I), dyl)-2-hydroxyethoxy]benzyl ]-2,4-thiazolidinedione (M-II), tyl-2-pyridyl)ethoxy]benzyl]-2,4-thiaz olidinedione (M-III), yl)-2-pyridyl]ethoxy]benzyl]-2,4-thiazolidinedio ne (M-IV), and oxy-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-V ), and oxy-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-VI). Piog litazone is considered to be metabolized by cleavage of aliphatic C-O bond to lead to M-I, hydroxylation of aliphatic methylene groups to fo rm M-II and M-IV, oxidation of M-IV to give M-III. oxidation of the et hyl group to form M-V, and oxidative loss of the terminal carbon to le ad to M-VI. Furthermore, part of metabolites exist as conjugated form. Among the conjugates, M-IV conjugated with sulfuric acid and M-V conj ugated with taurine were identified.