Determination of metabolic profile of novel triethylamine containing thiophene S006‐830 in rat, rabbit, dog and human liver microsomes. Issue 2 (28th April 2015)

• Record Type: Journal Article
• Authors: Hidau, Mahendra Kumar; Singh, Yeshwant; Singh, Shio Kumar
• Is Part Of: Drug testing and analysis. Volume 8:Issue 2(2016:Feb.)
• Page Start: 180
• Page End: 188
• Publication Date: 2015-04-28
• Subjects: enzyme kinetics -- reaction phenotyping -- intrinsic clearance -- metabolic stability -- liver microsomes; Drugs -- Analysis -- Periodicals; Drug testing -- Periodicals; Chemistry, Forensic -- Periodicals; 615.1901
• DOI: 10.1002/dta.1802
• Languages: English
• ISSNs: 1942-7603

Abstract

Abstract : CDRI S006‐830 is a potent triethylamine containing thiophene antitubercular compound of the Central Drug Research Institute, India. The present study aimed to conduct comprehensive metabolic investigations of CDRI S006‐830 to corroborate its preclinical investigations. Preliminary metabolic investigations were performed to assess the metabolic stability, enzyme kinetics, reaction phenotyping, and metabolite identification of CDRI S006‐830 in rat, rabbit, dog, and human liver microsomes using liquid chromatography with mass spectrometry. The observed in vitro t1/2 and Clint values were 9.9 ± 1.29, 4.5 ± 0.52, 4.5 ± 0.86, 17 ± 5.21 min and 69.60 ± 8.37, 152.0 ± 17.26, 152.34 ± 27.63, 33.62 ± 21.04 μL/min/mg in rat, rabbit, dog and human liver microsomes respectively. These observations suggested that CDRI S006‐830 rapidly metabolized in the presence of NADPH in liver microsomes of rat, rabbit and dog while moderately metabolized in human liver microsomes. It was observed that CDRI S006‐830 exhibited monophasic Michaelis–Menten kinetics. The metabolism of CDRI S006‐830 was primarily mediated by CYP3A4 and was deduced by CYP reaction phenotyping with known potent inhibitors. CYP3A4 involvement was also confirmed by cDNA‐expressed recombinant human isozyme activity with different CYPs. Four major phase‐I metabolites of S006‐830, (M‐1 to M‐4) were detected in rat, rabbit, dog (except M4) and human liver microsomes. Copyright © 2015 John Wiley & Sons, Ltd. Abstract : A comprehensive metabolic profiling in rat, rabbit, dog and human liver microsomes using liquid chromatography with mass spectrometry explored cytochrome 3A4 as the primary mediator of CDRI S006–830 metabolism with four major phase I metabolites.