In vivo metabolic investigation of cetilistat in normal versus pseudo-germ-free rats using UPLC-QTOFMS/MS and in silico toxicological evaluation of its metabolites.

Autor: Tiwari SS; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India., Mukesh S; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India., Sangamwar AT; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India., Talluri MVNK; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Jazyk: angličtina
Zdroj: Biomedical chromatography : BMC [Biomed Chromatogr] 2020 Aug; Vol. 34 (8), pp. e4860. Date of Electronic Publication: 2020 May 22.
DOI: 10.1002/bmc.4860
Abstrakt: Cetilistat (CET) is a pancreatic lipase inhibitor approved for management of obesity after the serious adverse effects exhibited by its analogue orlistat. Exhaustive literature review reveals lack of comprehensive reports on its biotransformation. With a view to study the same, the present study reports the identification and characterization of metabolites of CET in rats using UPLC-MS/MS. As the small intestine is the site of action for CET, it is important that the role of microbial flora in the metabolism of CET be explored. To achieve this, the metabolic profile of CET was compared between normal and pseudo-germ-free rats. The study involved the administration of a drug suspension to male Sprague-Dawley pseudo-germ-free and normal untreated rats followed by collection of urine, feces, and blood at specific intervals. Sample preparation was performed using liquid-liquid extraction and concentration of samples followed by analysis using LC-MS/MS. Finally, an in silico study was performed on the drug and metabolites to predict their toxicological properties using ADMET Predictor TM software. Four metabolites of CET were observed in in vivo matrices. As expected, significant changes were observed both qualitatively and quantitatively, implying that formation of metabolites was both CYP enzymes and gut microflora mediated.
(© 2020 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
Externí odkaz: