Studies on the metabolism of the new antidiabetic agent pioglitazone. Identification of metabolites in rats and dogs

Abstract

Metabolic studies of pioglitazone (CAS 105355-27-9, AD-4833), a new antidiabetic agent, in rats and dogs using liquid chromatography/tandem mass spectrometry and 1H-nuclear magnetic resonance led to characterization of the following metabolites: the parent compound, (±)-5-(p-hydroxybenzyl)-2,4-thiazolidinedione (M-I), (±)-5-[p-[2-(5-ethyl-2-pyridyl)-2-hydroxyethoxy]benzyl]-2,4-thiazolid inedione (M-II), (±)-5-[p-[2-(5-acetyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-III), (±)-5-[p-[2-[5-(1-hydroxyethyl)-2-pyridyl]ethoxy]benzyl]-2,4-thiazoli dinedione (M-IV), (±)-5-[p-[2-(5-carboxymethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidin edione (M-V), and (±)-5-[p-[2-(5-carboxy-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-VI). Pioglitazone is considered to be metabolized by cleavage of aliphatic C-O bond to lead to M-I, hydroxylation of aliphatic methylene groups to form M-II and M-IV, oxidation of M-IV to give M-III, oxidation of the ethyl group to form M-V, and oxidative loss of the terminal carbon to lead to M-VI. Furthermore, part of metabolites exist as conjugated form. Among the conjugates, M-IV conjugated with sulfuric acid and M-V conjugated with taurine were identified.