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    Pharmacokinetics and Pharmacodynamics of Loperamide in mdr1a (+/+) and mdr1a (-/-) Mice

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    poster presentation (95.35Kb)
    Date
    2004
    Author
    Olson, Emily R.
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    Abstract
    P-glycoprotein (P-gp), is a transmembrane protein located in the bloodbrain barrier (BBB) that limits access of a variety of drugs, including HIVprotease inhibitors, immunosuppresants chemotherapeutic compounds and opioids, to the CNS. P-gp is thought to play a protective role by excluding substrates from entry into the bloodstream and by facilitation substrate elimination from the body and from penetrating into a variety of “sanctuary” tissue spaces representing organs that are prone to toxic insult such as the brain. Loperamide (Immodium-AD) is a unique member of the opioid family because it exhibits pronounced peripheral affects while remaining relatively impermeable at the BBB and therefore ineffective in the CNS. Previous work with morphine, methadone and loperamide in P-gp competent [mdr1a (+/+)] and deficient [mdr1a (-/-)] mice have demonstrated that mice lacking P-gp exhibit enhanced brain concentrations and analgesic effects. A comprehensive in vivo description of the ability of P-gp to modulate analgesia, and in particular the degree to which changes in analgesia correlate with altered distribution of loperamide within the body, is lacking. The primary objective of the present study was to assess the role of P-gp in the pharmacokinetics (PK; drug concentrations over time) and pharmacodynamics (PD; ability to minimize apparent discomfort in the presence of painful stimuli) of loperamide.
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    http://hdl.handle.net/10920/4383
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