In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1
Author(s)
Type
Journal Article
Abstract
1. In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterialβ-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.2. The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively.3. The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation,deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomalincubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites werecharacterised, 9 for human, and 11 for mouse and rat. 4. Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasicdecline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liverblood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mLwere measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oralbioavailability of Inh 1 in the mouse was ca. 26%.
Date Issued
2024-07
Date Acceptance
2024-05-16
Citation
Xenobiotica: the fate of foreign compounds in biological systems, 2024, 54 (6), pp.304-315
ISSN
0049-8254
Publisher
Taylor and Francis Group
Start Page
304
End Page
315
Journal / Book Title
Xenobiotica: the fate of foreign compounds in biological systems
Volume
54
Issue
6
Copyright Statement
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
this is an open access article distributed under the terms of the creative commons attribution-noncommercial-noDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in anyway. the terms on which this article has been published allow the posting of the accepted Manuscript in a repository by the author(s) or with their consent.
this is an open access article distributed under the terms of the creative commons attribution-noncommercial-noDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in anyway. the terms on which this article has been published allow the posting of the accepted Manuscript in a repository by the author(s) or with their consent.
Identifier
https://www.tandfonline.com/doi/full/10.1080/00498254.2024.2357765
Subjects
CLEARANCE
CPT-11
desulphurisation
DRUGS
ENTEROPATHY
glucuronidation
glutathione conjugation
HEPATOCYTES
INHIBITION
Life Sciences & Biomedicine
O-deethylation
oxidative metabolism
Pharmacology & Pharmacy
PREDICTION
Science & Technology
TOXICITY
Toxicology
Publication Status
Published
Date Publish Online
2024-06-12