In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1

Abstract

ABSTRACT 1. In vitro 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. 2. The intrinsic clearances of Inh 1 in human, mouse and rat hepatic microsomes were 30.9, 67.8 and 201 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 microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, eighteen metabolites were characterised, nine for human, and eleven for mouse and rat. 4. Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 declined bi-exponentially with a terminal elimination half-life of 0.91 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 ng/ml were measured 0.5 hr post dose, declining to under 10 ng/ml at 8 hr post dose. The absolute oral bioavailability of Inh 1in the mouse was ca. 26%.