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Drug Metab Dispos. 2018 Apr 4. pii: dmd.117.079012. doi: 10.1124/dmd.117.079012. [Epub ahead of print]

New Pioglitazone Metabolites and Absence of Opened Ring Metabolites in New N-substituted Thiazolidinedione.

Author information

1
Universidade Federal do Parana.
2
Faculdade de Ciencias Farmaceuticas - Universidade Estadual Paulista (UNESP).
3
Universidade Federal de Pernambuco.
4
Universidade Federal do Parana; pontarolo@ufpr.br.

Abstract

Thiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

KEYWORDS:

drug design; drug toxicity; mass spectrometry/MS; metabolite identification; peroxisome proliferator-activated receptors; pharmacokinetics

PMID:
29618574
DOI:
10.1124/dmd.117.079012

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