<i>In vitro</i> and <i>in vivo</i> studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1
Creators: name: Kerins, Anna
name: Butler, Phil
name: Riley, Rob
name: Koszyczarek, Marta
name: Smith, Caroline
name: Cruickshank, Faye
name: Madgula, Vamsi
name: Naik, Nilkanth
name: Redinbo, Matthew R.
name: Wilson, Ian D.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: Environmental Sciences not elsewhere classified
subject: Chemical Sciences not elsewhere classified
subject: Developmental Biology
subject: Marine Biology
subject: Hematology
subject: Virology

description: <i>In vitro</i> studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-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.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201<b> </b>µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129<b> </b>µL/min/10<sup>6</sup> cells were seen for human, mouse and rat, respectively.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 microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat.Following IV administration to mice (3<b> </b>mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91<b> </b>h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495<b> </b>ng/mL were measured 0.5<b> </b>h post dose, declining to under 10<b> </b>ng/mL at 8<b> </b>h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%. <i>In vitro</i> studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-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. The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201<b> </b>µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129<b> </b>µL/min/10<sup>6</sup> cells were seen for human, mouse and rat, respectively. 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 microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat. Following IV administration to mice (3<b> </b>mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91<b> </b>h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495<b> </b>ng/mL were measured 0.5<b> </b>h post dose, declining to under 10<b> </b>ng/mL at 8<b> </b>h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.