Characterization of a Novel 99mTc-Carbonyl Complex as a Functional Probe of MDR1 P-Glycoprotein Transport Activity

Dyszlewski, Mary; Blake, Helen M.; Dahlheimer, Julie L.; Pica, Christina M.; Piwnica‐Worms, David

doi:10.1162/153535002753395680

Cited by 27 publications

(13 citation statements)

References 42 publications

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“…We bred APPsw +/-mice to mdr1a/b -/-animals to produce littermate mice that were positive for the (19). In animals of similar age that expressed the APPsw +/-transgene, brain penetration of the tracer was also increased by approximately 3.5-fold in Pgp-null animals compared with those expressing Pgp (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

Cirrito

Deane

Fagan

et al. 2005

Journal of Clinical Investigation

575

469

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Section: Resultsmentioning

confidence: 99%

P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

Cirrito

Deane

Fagan

et al. 2005

Journal of Clinical Investigation

575

469

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“…At our institution the imaging agents used for cardiac imaging are 99m Tc-sestamibi (Tc-99m) radionuclide (778 D) for SPECT imaging and Iodixanol (Visipaque) (1550 D) for CT imaging. Tc-99m has both a hydrophilic cation portion and an isonitrile hydrophobic section that allows cell membrane uptake but has previously been noted as a substrate for the ATP binding cassette transporter, P-glycoprotein [29–32]. Its cellular uptake is strongly dependent on mitochondrial activity and the integrity of the cell membrane but its distribution, retention and clearance within viable tissue is very slow [33].…”

Section: Introductionmentioning

confidence: 99%

The effect of regadenoson on the integrity of the human blood–brain barrier, a pilot study

et al. 2017

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Regadenoson is an FDA approved adenosine receptor agonist which increases blood-brain barrier (BBB) permeability in rodents. Regadenoson is used clinically for pharmacologic cardiac stress testing using SPECT or CT imaging agents that do not cross an intact BBB. This study was conducted to determine if standard doses of regadenoson transiently disrupt the human BBB allowing higher concentrations of systemically administered imaging agents to enter the brain. Patients without known intracranial disease undergoing clinically indicated pharmacologic cardiac stress tests were eligible for this study. They received regadenoson (0.4 mg) followed by brain imaging with either Tc-sestamibi for SPECT or visipaque for CT imaging. Pre- and post-regadenoson penetration of imaging agents into brain were quantified [SPECT: radioactive counts, CT: Hounsfield units (HU)] and compared using a matched-pairs t-test. Twelve patients (33% male, median 60 yo) were accrued: 7 SPECT and 5 CT. No significant differences were noted in pre- and post-regadenoson values using mean radionuclide counts (726 vs. 757) or HU (29 vs. 30). While animal studies have demonstrated that regadenoson transiently increases the permeability of the BBB to dextran and temozolomide, we were unable to document changes in the penetration of contrast agents in humans with intact BBB using the FDA approved doses of regadenoson for cardiac evaluation. Further studies are needed exploring alternate regadenoson dosing, schedules, and studies in patients with brain tumors; as transiently disrupting the BBB to improve drug entry into the brain is critical to improving the care of patients with CNS malignancies.

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“…P-glycoprotein is thought to be involved in both the BBB and the blood-CSF barrier, but data regarding its comparative function at these separate locations are scarce. We decided to use this canine model to assess brain and CSF concentrations of 99m Tc-sestamibi, a radiolabeled P-glycoprotein substrate (Dyszlewski et al, 2002), in ABCB1 wild-type and ABCB1-1⌬ dogs. Serial nuclear scintigraphic imaging was used to assess uptake of 99m Tcsestamibi in brain tissue, whereas direct measurement of radioactivity FIG.…”

Section: Results Of Neurological Examination 6 H After Loperamide Admmentioning

confidence: 99%

P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model

Mealey

Greene²,

Bagley³

et al. 2008

Drug Metab Dispos

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ABSTRACT:P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1⌬) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1⌬ dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate 99m Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.

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Characterization of a Novel 99mTc-Carbonyl Complex as a Functional Probe of MDR1 P-Glycoprotein Transport Activity

Cited by 27 publications

References 42 publications

P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model

The effect of regadenoson on the integrity of the human blood–brain barrier, a pilot study

P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model

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