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

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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.

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Acknowledgments

This work was supported in part by fellowship support T32GM066691 in Johns Hopkins Clinical pharmacology training program (Sadhana Jackson). The project described was supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (National Institutes of Health grants P30 CA006973 and UL1 TR 001079, and Shared Instrument Grant 1S10RR026824-01). Grant Number UL1 TR 001079 is from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health, and National Institutes of Health Roadmap for Medical Research.

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Authors and Affiliations

  1. Brain Cancer Program, Johns Hopkins University, David H. Koch Cancer Research Building II, 1550 Orleans Street, Room 1M16, Baltimore, MD, 21287, USA

    Sadhana Jackson & Stuart A. Grossman

  2. 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

    Nicole M. Anders, Teresia M. Wanjiku & Michelle A. Rudek

  3. 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

    Antonella Mangraviti, Eric W. Sankey, Ann Liu, Henry Brem & Betty Tyler

  4. 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

    Henry Brem

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  1. Sadhana Jackson
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  2. Nicole M. Anders
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Correspondence to Stuart A. Grossman.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Jackson, S., Anders, N.M., Mangraviti, A. et al. The effect of regadenoson-induced transient disruption of the blood–brain barrier on temozolomide delivery to normal rat brain. J Neurooncol 126, 433–439 (2016). https://doi.org/10.1007/s11060-015-1998-4

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  • DOI: https://doi.org/10.1007/s11060-015-1998-4

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