A new model of systemic drug rescue based on permeability characteristics of the blood-brain barrier in intracerebral abscess-bearing rats

Abstract

✓The authors report the results of their investigation of a systemic drug rescue method using antibody to a therapeutic drug based on the differential permeability of the blood-brain barrier to low- and high-molecular-weight compounds. Rats bearing intracerebral abscesses initially received systemic [125I]-gentamicin (Mr 462) followed 60 minutes later by specific gentamicin antiserum (immune group) or normal rabbit serum (nonimmune group). Animals receiving antigentamicin immunoglobulin G (IgG, Mr 150,000) demonstrated 90% binding of serum gentamicin. Immunoprecipitation of serum samples with protein A-Sepharose demonstrated that the increased binding of gentamicin in immune animals was due to antigen binding with antigentamicin IgG. By contrast, the percent of gentamicin bound to antibody within the brain did not differ between immune and nonimmune groups, implying that high-molecular-weight IgG was excluded from the brain and brain lesion. Significant differences in gentamicin deliveries were noted in the abscess, brain around the abscess, brain distant from the abscess, and normal brain areas. In contrast, analysis of comparable brain areas demonstrated no significant differences in gentamicin delivery between immune and nonimmune animals, indicating that the systemic presence of gentamicin antibody did not alter central nervous system delivery of unbound drug. These findings suggest the possibility of a drug rescue method using antidrug IgG, based on the differential permeability of the blood-brain barrier to drug versus antibody. While the present work was developed in a brain abscess model, the drug rescue method may also be applicable in the management of intracerebral tumors.