Preclinical safety studies of glucose oxidase.
The purpose of this study was to develop preclinical safety data regarding the toxicologic and pharmacokinetic properties of glucose oxidase. Groups of adult BALB/c mice were injected with four doses of the enzyme ranging from 0.125 U of glucose oxidase/g b.wt. to 1 U/g b.wt., and the following responses were measured: survival, methemoglobin, glucose, blood urea nitrogen, creatine phosphokinase, erythrocyte count and body weight. We also compared the biodistribution of the enzyme in mice to the biodistribution of glucose oxidase conjugated to a monoclonal antibody. Finally, we assessed the histopathologic changes produced in mice by glucose oxidase and the binding of the enzyme to snap-frozen, human autopsy tissues. As expected, the acute toxicity of glucose oxidase was primarily due to methemoglobinemia (mean concentration 36% at the highest dose) and transient hypoglycemia (as low as 35 mg/dl). Furthermore, conjugated and unconjugated glucose oxidase had a blood half-life of less than 2 hr and concentrated in the liver and spleen. On the basis of our studies, we conclude that glucose oxidase has reasonably predictable toxicities and is, therefore, safe for human trials. The rapid uptake of conjugated and unconjugated glucose oxidase by the liver and spleen, however, may significantly limit the therapeutic targeting of glucose oxidase.
Pathology Department, University of California, Irvine.
M
M
Samoszuk
D
D
Ehrlich
E
E
Ramzi
D000818:Animals; D004353:Drug Evaluation, Preclinical; D004795:Enzyme Stability; D005260:Female; D005949:Glucose Oxidase / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000922:Immunotoxins / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014018:Tissue Distribution
D000922:Immunotoxins; D005949:Glucose Oxidase