title: 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 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-thiazolidinedione (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-thiazolidinedione (M-IV), (+/-)-5-[p-[2-(5- carboxymethyl-2-pyridyl)ethoxy]- benzyl]-2,4-thiazolidinedione (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-IV. 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.
authors.affiliation: Drug Analysis and Pharmacokinetics Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyota
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: Y
authors.initials: Y
authors.lastname: Maeshiba
authors.forename: A
authors.initials: A
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: M
authors.initials: M
authors.lastname: Motohashi
authors.forename: S
authors.initials: S
authors.lastname: Tanayama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002853:Chromatography, Liquid; D004285:Dogs; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007441:Intubation, Gastrointestinal; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics*; D045162:Thiazolidinediones
chemical_list: D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077205:Pioglitazone