title: The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.
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.
authors.affiliation: Brain Cancer Program, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 1M16, Baltimore, MD, 21287, USA.
authors.forename: Sadhana
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Chemical Therapeutics and Analytical Pharmacology Core Laboratory, Johns Hopkins University, Bunting-Blaustein Cancer Research Building I, 1650 Orleans Street, CRB1 Room 1M52, Baltimore, MD, 21231, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Anders
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mangraviti
authors.affiliation: Chemical Therapeutics and Analytical Pharmacology Core Laboratory, Johns Hopkins University, Bunting-Blaustein Cancer Research Building I, 1650 Orleans Street, CRB1 Room 1M52, Baltimore, MD, 21231, USA.
authors.forename: Teresia M
authors.initials: TM
authors.lastname: Wanjiku
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Sankey
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.|Departments of Ophthalmology, Oncology and Biomedical Engineering, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 2M45, Baltimore, MD, 21287, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Chemical Therapeutics and Analytical Pharmacology Core Laboratory, Johns Hopkins University, Bunting-Blaustein Cancer Research Building I, 1650 Orleans Street, CRB1 Room 1M52, Baltimore, MD, 21231, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Brain Cancer Program, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 1M16, Baltimore, MD, 21287, USA. grossman@jhmi.edu.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D053719:Tandem Mass Spectrometry; D000077204:Temozolomide; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011687:Purines; D011720:Pyrazoles; C430916:regadenoson; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Blood–brain barrier; Brain metastases; Brain tumor; Pharmacology; Regadenoson; Temozolomide