Identification of novel metabolites of pioglitazone in rat and dog

Z. Shen Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

J. R. Reed Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

M. Creighton Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

D. Q. Liu Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

Y. S. Tang Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

D. F. Hora Departments of Comparative Medicine, Merck Research Laboratories, Rahway, NJ 07065, USA

W. Feeney Departments of Comparative Medicine, Merck Research Laboratories, Rahway, NJ 07065, USA

J. Szewczyk Departments of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA

R. Bakhtiar Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

R. B. Franklin Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

S. H. Vincent Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA

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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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Identification of novel metabolites of pioglitazone in rat and dog

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Identification of novel metabolites of pioglitazone in rat and dog

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