Pharmacokinetics of the natural antibiotic negamycin.

摘要: Abstract1. 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, pharmacokinetics pre-clinical species were determined.2. Negamycin has a dipeptide-like structure with logD7.4 < −1, causing low permeation into Caco-2 cells, low-oral bioavailability rats 6% low-plasma binding 10% mouse, rat, dog human plasma. Negamycin degradation rates microsomes hepatocytes predicted low-hepatic intrinsic clearance species, which was confirmed vivo where varied between 3.4 11.5 mL/min/kg virtually all cleared unchanged renally. The similar behavior multiple allowed the prediction systemic volume distribution humans using multiple-scaling methods physiological-based pharmacokinetic modeling simulation.3. Only 0.05–0.25% (mol/mol) ...