Perfusion and Molecular Modification of Idoxuridine to Alter Its Cerebrospinal Fluid Metabolism

Abstract

Two methods to deter the rapid intrathecal degradation of idoxuridine were investigated: (a) rapid drug perfusion through the ventricular system, and (b) modification of the molecule to its uronic acid derivative, 2′-deoxy-5-iodo-5′-uridinecarboxylic acid, to make it less susceptible to enzymatic digestion. Perfusion of idoxuridine through the ventricular system (ventriculocisternal) of dogs at 0.97ml/min saturated the metabolic pathway so that the outflow solution yielded a single spot (Rf 0.76) on TLC indicative of the intact molecule. The 125I-labeled uronic acid was synthesized from the 125I-labeled parent compound, and the labeled compounds were compared after their individual intracisternal injection in dogs. Since there was no difference in the disappearance rates, the stability of the uronic acid was, in fact, no greater than that of the parent compound in vivo. Ventricular perfusion of idoxuridine, however, seems a suitable means for increasing the amount of active drug delivered to central nervous system tumors and viral infections.