Determination of metabolic profile of novel triethylamine containing thiophene S006-830 in rat, rabbit, dog and human liver microsomes.
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.
Academy of Scientific and Innovative Research, New Delhi, 110001, India.|Pharmacokinetics & Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, -226031, India.
Mahendra Kumar
MK
Hidau
Pharmacokinetics & Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, -226031, India.
Yeshwant
Y
Singh
Pharmacokinetics & Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, -226031, India.
Shio Kumar
SK
Singh
D000818:Animals; D002138:Calibration; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004285:Dogs; D005021:Ethylamines / Q000378:metabolism* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013876:Thiophenes / Q000378:metabolism* / Q000493:pharmacokinetics*
D065607:Cytochrome P-450 Enzyme Inhibitors; D005021:Ethylamines; D013876:Thiophenes; C000611962:diisopropyl-(2-(4-((4-methoxyphenyl)thiophen-2-ylmethyl)phenoxy)ethyl)amine; C016162:triethylamine
enzyme kinetics; intrinsic clearance; liver microsomes; metabolic stability; reaction phenotyping