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1. ETX0914 is a novel bacterial topoisomerase inhibitor that has a novel mode-of-inhibition and is in clinical development for the treatment of infections caused byNeisseria gonorrhoeae. 2. Thein vitrobiotransformation studies of ETX0914 using mouse, rat, dog and human hepatocytes showed moderate intrinsic clearance in mouse and rat and low intrinsic clearance in dog and human. 3. Following intravenous administration of [14C]-ETX0914 in rats, the mean recovery of administered dose in urine, bile and feces was approximately 15%, 55% and 24%, respectively. Unchanged ETX0914 recovered in urine and bile was less than 5% of the dose, indicating that ETX0914 underwent extensive metabolism in rats. Metabolites M1, M2, M4, M6 and M12 detected in both rat and mouse urine samples were not detected in mouse urine when predosed with 1-aminobenzotriazole, indicating that these metabolites were cytochrome P450 mediated products. The major fecal metabolites observed in rats were not formed when ETX0914 was incubated with fresh feces from germ free rats under sterile condition or in incubations with rat intestinal microsome and cytosol, suggesting that most likely ETX0914 was directly excreted into gut lumen where metabolites were formed as intestinal microflora-mediated products. The major sites of metabolism by CYP enzymes were in the morpholine and oxazolidinone rings while it was benzisoxazole reduction with the gut microflora. [ABSTRACT FROM AUTHOR]

1. (2 R,4 S,4a S)-11-Fluoro-2,4-dimethyl-8-(( S)-4-methyl-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1'H-spiro [isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (AZ11) is a novel mode-of-inhibition bacterial topoisomerase inhibitor that entered preclinical development for the treatment of Gram-positive bacteria infection. 2. The in vitro biotransformation studies of AZ11 using mouse, rat, dog and human hepatocytes showed low-intrinsic clearance in all species attributed to microsomal metabolism. 3. After a single intravenous administration of [14C]AZ11 in bile duct cannulated rats, the mean percentage of dose recovered in rat urine, bile and feces was approximately 18, 36 and 42%, respectively. Unchanged AZ11 recovered in rat urine and bile was less than 9% of the dose, indicating that AZ11 underwent extensive metabolism in rats. 4. The most abundant in vivo metabolite detected in urine and bile was M1 formed via ring opening on the piperidine and morpholine rings accounting for 20% of the administered dose. The major fecal metabolite was M5, which accounted for approximately 32% of administered dose. M5 was not formed when AZ11 incubated with rat intestinal microsomes and cytosol but was formed when incubated with fresh rat feces, suggesting that unchanged AZ11 was directly excreted into gut lumen where M5 formed as an intestinal microflora-mediated product. This process could have significant impact on bioavailability or exposure of AZ11 in rat. [ABSTRACT FROM AUTHOR]