Identification of novel metabolites of pioglitazone in rat and dog

作者：Z. Shen, James R. Reed, Mellissa Creighton, D. Q. Liu, Yiling Tang, D. F. Hora, William P. Feeney, Jason W. Szewczyk, Ray Bakhtiar, Ronald B. Franklin, Stella Vincent · 发表于：Xenobiotica · 年份：2003 · DOI：10.1080/0049825031000085951 · 被引用次数：39 · 研究领域：Peroxisome Proliferator-Activated Receptors、Receptor Mechanisms and Signaling、Drug Transport and Resistance Mechanisms

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.