Pharmacokinetics of the natural antibiotic negamycin

Abstract

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 logD_7.4 < −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.

• In vitro ADME
• pharmacokinetics
• prediction

Acknowledgements

All authors are past or current employees of AstraZeneca R&D Boston. They acknowledge Drs Minli Zhang, Adam J. Dudley and Harish Shankaran for helpful discussion, Aixiang Xue for mouse and rat studies and Pharmaron (Beijing, China) for plasma protein binding and Caco-2 cell permeability assays.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.