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Mass Balance Study of the Engineered Cationic Antimicrobial Peptide, WLBU2, Following a Single Intravenous Dose of 14C-WLBU2 in Mice

[ Vol. 15 , Issue. ]

Author(s):

Jan H. Beumera*, Jianxia Guo, Evan C. Ray, Jonas Scemama, Robert A. Parise, Berthony Deslouches, Jonathan D. Steckbeck, Ronald C. Montelaro and Julie L. Eiseman Pages 1-10 (10)

Abstract:


Background: To address multidrug resistance we developed engineered cationic antimicrobial peptides (eCAPs). Lead eCAP WLBU2 displays potent activity against drug-resistant bacteria and effectively treats lethal bacterial infections in mice reducing bacterial loads to undetectable levels in diverse organs.

Objective: To support development of WLBU2, we conducted a mass balance study.

Methods: CD1 mice were administered 10, 15, 20 and 30 mg/kg QDx5 WLBU2 or a single dose of [14C]-WLBU2 at 15 mg/kg IV. Tolerability, tissue distribution and excretion were evaluated with liquid scintillation and HPLCradiochromatography.

Results: The maximum tolerated dose of WLBU2 is 20 mg/kg IV. We could account for greater than >96% of the radioactivity distributed within mouse tissues at 5 and 15 min. By 24 h, only ~40-50% of radioactivity remained in the mice. The greatest % of the dose was present in liver, accounting for ~35% of radioactivity at 5 and 15 min, and ~ 8% of radioactivity remained at 24 h. High radioactivity was also present in kidneys, plasma, red blood cells and lungs, while less than 0.2% of radioactivity was present in brain, fat, or skeletal muscle. Urinary and fecal excretion accounted for 12.5 and 2.2% of radioactivity at 24 h.

Conclusion: WLBU2 distributes widely to mouse tissues and is rapidly cleared with a terminal radioactivity half-life of 22 h, a clearance of 27.4 mL/h/kg, and a distribution volume of 0.94 L/kg. At 2-100 µg-eq/g, the concentrations of 14CWLBU2 appear high enough in the tissues to account for inhibition of microbial growth.

Keywords:

Engineered cationic peptide, radioactivity, pharmacokinetics, mass balance, antimicrobial, disposition.

Affiliation:

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, 3501 Terrace Street. Pittsburgh, PA 15261, Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave. Pittsburgh, PA 15213, Department of Medicine Renal-Electrolyte Division, University of Pittsburgh School of Medicine, 3550 Terrace Street. Pittsburgh, PA 15261, Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave. Pittsburgh, PA 15213, Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave. Pittsburgh, PA 15213, Department of Microbiology and Molecular Genetics, University of Pittsburgh, 3550 Terrace Street. Pittsburgh, PA 15261, Department of Microbiology and Molecular Genetics, University of Pittsburgh, 3550 Terrace Street. Pittsburgh, PA 15261, Department of Microbiology and Molecular Genetics, University of Pittsburgh, 3550 Terrace Street. Pittsburgh, PA 15261, Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave. Pittsburgh, PA 15213



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