TR-09 * THE EFFECT OF REGADENOSON-INDUCED TRANSIENT DISRUPTION OF THE BLOOD BRAIN BARRIER ON TEMOZOLOMIDE DELIVERY TO RAT BRAIN PARENCHYMA

Abstract

PURPOSE: The blood-brain barrier (BBB) poses a serious challenge to effective delivery of systemically administered agents to the central nervous system. Temozolomide is the only systemically delivered chemotherapeutic agent to significantly improve survival in patients with glioblastoma. Brain temozolomide concentrations are only 20% of that in blood. Regadenoson is an FDA approved adenosine receptor agonist that transiently disrupts rodent's BBB allowing dextran (70 kD) brain entry. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brains. METHODS: Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing female F344 rats. Sixty to 90 minutes later two-thirds of the animals received a single dose of intravenous regadenoson. The animals were sacrificed 120 or 360 minutes after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. RESULTS: At 120 minutes, brain temozolomide concentrations were significantly higher when given with regadenoson vs. alone (8.1 ± 2.7 µg/g and 5.1 ± 3.5 µg/g, P < 0.05), with a similar trend in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). 360 minutes after temozolomide administration brain and brain:plasma were increased without statistical significance. There was no difference in plasma temozolomide concentration with or without regadenoson. CONCLUSION: These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without changing plasma temozolomide concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents can potentially improve the efficacy of therapeutic agents used in patients with brain tumors and other neurologic disorders.