In vitro and in vivo metabolism of 14C-AZ11, a novel inhibitor of bacterial DNA gyrase/type II topoisomerase.

Abstract1. (2R,4S,4aS)-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 acco...