The effect of hyperosmotic blood-brain barrier disruption on blood-to-tissue transport in ENU-induced gliomas.

Hyperosmotic blood-brain barrier disruption transiently increases the rate of blood-to-tissue transport of water-soluble compounds to normal brain and has been used in brain tumor patients to increase the delivery of chemotherapeutic drugs. This method remains controversial; debate concerns the extent to which it increases drug delivery to brain tumors. Ethylnitrosourea (ENU)-induced gliomas in rats have the lowest rate of blood-to-tissue transfer of the water-soluble compound alpha-aminoisobutyric acid of all experimental brain tumors studied to date. To gain further understanding about the effects of hyperosmotic blood-brain barrier disruption in brain tumors, we measured the unidirectional blood-to-tissue transfer constant of alpha-aminoisobutyric acid in ENU-induced brain tumors in rats after hyperosmotic disruption. Hyperosmotic blood-brain barrier disruption with 1.6 osmolar mannitol resulted in an averaged whole-tumor transfer constant of 0.013 +/- 0.003 (standard error) mL/(g/min), compared to a transfer constant of 0.007 +/- 0.002 mL/(g/min) for ENU-induced gliomas in the contralateral undisrupted hemisphere, a difference that was not significant. In contrast, hyperosmotic blood-brain barrier disruption produced a large and significant increase in the transfer constant of alpha-aminoisobutyric acid in tumor-free cortex (from 0.002 +/- 0.001 to 0.05 +/- 0.011 mL/[g/min]) and in tumor-free corpus callosum (from 0.001 +/- 0.003 to 0.017 +/- 0.005 mL/[g/min]). Hyperosmotic blood-brain barrier disruption does not appear to be an efficient method with which to increase the rate of delivery of water-soluble drugs to brain tumors but does result in a significant increase in the delivery rate of these drugs to normal brain tissue.