The in vitro metabolism and in vivo pharmacokinetics of the bacterial β-glucuronidase inhibitor UNC10201652.

1) In vitro incubation of the bacterial β-glucuronidase inhibitor UNC10201652 (4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine) with mouse, rat, and human liver microsomes and hepatocytes generated metabolites at multiple sites via deethylations, oxidations and glucuronidation.2) Two UNC10201652 metabolites were detected in human, and four in mouse and rat liver microsomal incubations. Intrinsic clearances of UNC10201652 in human, mouse, and rat liver microsomes were 48.1, 115, and 194 µL/min/mg respectively.3) Intrinsic clearances for human, mouse, and rat hepatocytes were 20.9, 116, and 140 µL/min/106 cells respectively and twenty four metabolites were characterized: nine for human and eleven for both rodent species.5) Plasma clearance was 324.8 mL/min/kg with an elimination half-life of 0.66 h following IV administration of UNC10201652 to Swiss Albino mice (3 mg/kg). Pre-treatment with 1-aminobenzotriazole (ABT) decreased clearance to 127.43 mL/min/kg, increasing the t1/2 to 3.66 h.5) Comparison of profiles after oral administration of UNC10201652 to control and pre-treated mice demonstrated a large increase in Cmax (from 15.2 ng/mL to 184.0 ng/mL), a delay in Tmax from 0.25 to 1 hr and increased AUC from 20.1 to 253 hr.ng/ml. ABT pre-treatment increased oral bioavailability from 15% to >100% suggesting that CYP450's contributed significantly to UNC10201652 clearance in mice.