Identification of novel metabolites of pioglitazone in rat and dog
Authors:
- Z. ShenZSZ. Shen
- J. R. ReedJRJ. R. Reed
- M. CreightonMCM. Creighton
- D. Q. LiuDLD. Q. Liu
- Y. S. TangYTY. S. Tang
- D. F. HoraDHD. F. Hora
- W. FeeneyWFW. Feeney
- J. SzewczykJSJ. Szewczyk
- R. BakhtiarRBR. Bakhtiar
- R. B. FranklinRFR. B. Franklin
- S. H. VincentSVS. H. Vincent
- 1 January 2003
- journal article
- research article
- Published by Taylor & Francis in Xenobiotica
- Vol. 33 (5) , 499-509
Abstract
1. Four new metabolites of pioglitazone were identified by liquid chromatography-mass spectrometry (LC-MS/MS) as being formed by hydroxylation (M-VII and M-VIII), opening of the thiazolidinedione ring (M-X) and by desaturation of the terminal ethyl side chain or tether ethoxy moiety (M-IX), respectively. The structure of one of the hydroxylated metabolites (M-VII) was confirmed by chemical modification using the Jones reaction. 2. Oxidative cleavage of the thiazolidinedione ring is a novel pathway not previously reported for pioglitazone. 3. The hydroxylated M-VII was detected in incubations with rat, dog and human liver and kidney microsomes, and in plasma from rats and dogs dosed orally with [(3)H]pioglitazone. 4. The carboxylic acid derivative of M-VII (M-V) and its taurine conjugate were the major radioactive components in dog bile.Keywords
This publication has 11 references indexed in Scilit:
- A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitusClinical Therapeutics, 2001
- New Oral Therapies for Type 2 Diabetes Mellitus: The Glitazones or Insulin SensitizersAnnual Review of Medicine, 2001
- Studies on the Metabolism of Troglitazone to Reactive Intermediates in Vitro and in Vivo. Evidence for Novel Biotransformation Pathways Involving Quinone Methide Formation and Thiazolidinedione Ring ScissionChemical Research in Toxicology, 2000
- Thiazolidinediones: A Comparative Review of Approved UsesDiabetes Technology & Therapeutics, 2000
- Direct Oxidation of Primarytert-Butyldimethylsilyl Ethers to Carboxylic Acids with Jones ReagentSynthetic Communications, 1996
- Synthesis and Biological Activity of Metabolites of the Antidiabetic, Antihyperglycemic Agent PioglitazoneJournal of Medicinal Chemistry, 1996
- Determination of pioglitazone in dog serum using solid-phase extraction and high-performance liquid chromatography with ultraviolet (229 nm) detectionJournal of Chromatography B: Biomedical Sciences and Applications, 1989
- Metabolic activation of valproic acid and drug-mediated hepatotoxicity. Role of the terminal olefin, 2-n-propyl-4-pentenoic acidChemical Research in Toxicology, 1988
- Oxidative cleavage of 1,2-glycols and α-hydroxy ketones with the ag]Tetrahedron Letters, 1988
- Measurement of protein using bicinchoninic acidAnalytical Biochemistry, 1985