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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]

4-Amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide (AZD6280) is a selective GABA-Aα2/3 receptor modulator under development for the treatment of generalized anxiety disorders. Absorption, metabolism, and excretion of [14C]-AZD6280 was studied in rats following a single oral (7 mg/kg) or intravenous (i.v., 1 mg/kg) administration of [14C]-AZD6280. The results from the bile duct-cannulated study revealed that AZD6280 was well-absorbed in rats. The pharmacokinetic analysis was conducted using unlabelled parent drug that was rapidly absorbed (plasma Tmax ~1 h) and exhibited a mean apparent terminal half-life of ~4.2 h. The overall mean recoveries in the excreta were 98.6% and 100.3% after oral and i.v. administration of [14C]-AZD6280, respectively. The major route for elimination of [14C]-AZD6280 and its metabolites was through faeces. The radiochromatographic analysis of the excreta demonstrated that AZD6280 underwent extensive biotransformation. A total of 28 metabolites of AZD6280 were detected and profiled in urine, bile, and faeces in this study. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. Similar metabolite profiles were observed in rats given AZD6280 orally or intravenously. [ABSTRACT FROM AUTHOR]