The effect of regadenoson-induced transient disruption of the blood–brain barrier on temozolomide delivery to normal rat brain

Sadhana Jackson, Nicole M. Anders, Antonella Mangraviti, Teresia M. Wanjiku, Eric W. Sankey, Ann Liu, Henry Brem, Betty Tyler, Michelle A. Rudek, Stuart A. Grossman

Research output: Contribution to journalArticlepeer-review

Abstract

The blood–brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60–90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P < 0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60 % higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

Original languageEnglish (US)
Pages (from-to)433-439
Number of pages7
JournalJournal of neuro-oncology
Volume126
Issue number3
DOIs
StatePublished - Feb 1 2016

Keywords

  • Blood–brain barrier
  • Brain metastases
  • Brain tumor
  • Pharmacology
  • Regadenoson
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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