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    The Use of In Vitro and In Silico Technologies for Predicting Human Pharmacology and Toxicology of Carfentanil

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    Author
    Feasel, Michael
    0000-0001-7029-2764
    Advisor
    Randall, William R., Ph.D.
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    Carfentanil is an ultra-potent opioid of public health and chemical weapons defense concern. Exposure to carfentanil has been seen in both illicit drug use and in the resolution of a hostage situation in Moscow, Russia in 2002. While opioid pharmacology and toxicology are well researched topics, carfentanil remains unstudied relative to its clinically used counterparts like fentanyl. Similarly to fentanyl, carfentanil elicits is toxicity from central nervous system depression, largely in regions of the brain involved in spontaneous respiratory rhythmogenesis. By depressing the respiratory centers of the brain, respiratory failure can occur, and can lead to death. Carfentanil is of concern because it has demonstrated 100 times higher potency than its prototype, fentanyl, in analgesic assays in rodents. Carfentanil has very little human relevant data to indicate its toxicity in man for use in public health or chemical defense risk assessments. The present study was designed to test the hypothesis that carfentanil pharmacokinetic modeling could accurately reflect observed pharmacokinetics in vivo in a surrogate animal model, and be translated to a human equivalent predication of toxicity. Studies were carried out to assess opioid receptor sub-type specificity, potency, and efficacy. Carfentanil metabolism was studied in both rabbit and human liver microsomes to assess its intrinsic clearance. A metabolite identification study was undertaken to identify metabolites that could contribute to prolonged exposure or toxicity, and to generate a library of metabolites to be used in a forensic setting to identify carfentanil as a culprit agent in overdose or mass casualty exposures. Additionally, two key physicochemical properties of carfentanil were quantified in both rabbit and human blood: plasma protein binding and red blood cell - plasma partitioning. These properties have important roles in pharmacokinetic modeling, and can be used in a forensic setting to indicate where carfentanil can be found. Finally, these in vitro data were incorporated into an in silico physiologically based pharmacokinetic model to accurately predict in vivo pharmacokinetics seen in a surrogate species. This model was then used to translate to a human equivalent toxic dose.
    Description
    University of Maryland, Baltimore. Toxicology. Ph.D. 2017
    Keyword
    carfentanil
    PBPK
    Opioids
    Fentanyl
    Pharmacology
    Toxicology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/6764
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