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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. Negamycin exerts its antimicrobial activity by inhibiting bacterial protein synthesis and is efficacious in animal models of infection. In order to optimize negamycin exposure for therapeutic purposes, its pharmacokinetics in pre-clinical species were determined. 2. Negamycin has a dipeptide-like structure with log D7.4 < −1, causing low permeation into Caco-2 cells, low-oral bioavailability in rats of 6% and low-plasma protein binding of 10% in mouse, rat, dog and human plasma. Negamycin degradation rates in microsomes and hepatocytes predicted low-hepatic intrinsic clearance in pre-clinical species, which was confirmed in vivo where clearance varied between 3.4 and 11.5 mL/min/kg and virtually all negamycin was cleared unchanged renally. The similar behavior in multiple animal species allowed for the prediction of systemic clearance and volume of distribution in humans using multiple-scaling methods and physiological-based pharmacokinetic modeling and simulation. 3. Only 0.05-0.25% (mol/mol) of administered negamycin was recovered as 2-(1-methylhydrazinyl)acetic acid, a potential reactive metabolite, from rat and dog urine, respectively. 4. In summary, negamycin is a very polar molecule with low-plasma protein binding and low-oral bioavailability that is slowly and exclusively cleared into the urine. Its physicochemical properties make intravenous or intramuscular administration, or a derivative thereof, for therapeutic purposes most likely. [ABSTRACT FROM AUTHOR]