Identification of novel metabolites of pioglitazone in rat and dog |
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| Authors: | Shen Z Reed J R Creighton M Liu D Q Tang Y S Hora D F Feeney W Szewczyk J Bakhtiar R Franklin R B Vincent S H |
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| Affiliation: | Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. zhongzhou_shen@merck.com |
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| 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. |
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