PRECLINICAL SAFETY STUDIES OF GLUCOSE-OXIDASE

The purpose of this study was to develop preclinical safety data regar ding the toxicologic and pharmacokinetic properties of glucose oxidase . Groups of adult BALB/c mice were injected with four doses of the enz yme ranging from 0.125 U of glucose oxidase/g b.wt. to 1 U/g b.wt., an d the following responses were measured: survival, methemoglobin, gluc ose, blood urea nitrogen, creatine phosphokinase, erythrocyte count an d body weight. We also compared the biodistribution of the enzyme in m ice to the biodistribution of glucose oxidase conjugated to a monoclon al antibody. Finally, we assessed the histopathologic changes produced in mice by glucose oxidase and the binding of the enzyme to snap-froz en, 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 reas onably predictable toxicities and is, therefore, safe for human trials . The rapid uptake of conjugated and unconjugated glucose oxidase by t he liver and spleen, however, may significantly limit the therapeutic targeting of glucose oxidase.