Premium
Determination of metabolic profile of novel triethylamine containing thiophene S006‐830 in rat, rabbit, dog and human liver microsomes
Author(s) -
Hidau Mahendra Kumar,
Singh Yeshwant,
Singh Shio Kumar
Publication year - 2016
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.1802
Subject(s) - microsome , cyp3a4 , metabolite , pharmacology , cytochrome p450 , drug metabolism , chemistry , isozyme , enzyme , biochemistry , biology
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 t 1/2 and Cl int 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.