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    The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers

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    Authors
    Crowe, Andrew
    Wright, Cameron
    Date
    2011
    Type
    Journal Article
    
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    Citation
    Crowe, Andrew and Wright, Cameron. 2012. The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers. Xenobiotica. 42 (6): pp. 538-549.
    Source Title
    Xenobiotica
    DOI
    10.3109/00498254.2011.643256
    ISSN
    1366-5928
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/24956
    Collection
    • Curtin Research Publications
    Abstract

    1. Caco-2 cells were used to compare P-gp mediated efflux and passive permeability using bidirectional transport of 11 antihistamines. An efflux ratio >2 indicated active efflux, with PSC833 and GF120918 used as functional P-gp inhibitors. 2. Antihistamines were measured directly by HPLC or LC/MS. 3. Fexofenadine had an efflux ratio of 37, yet had negligible passive permeability, even in the presence of a pH gradient (0.1 × 10−6 cm/sec). Its precursor, terfenadine, had an efflux ratio of 2.5, while cetirizine, desloratadine and hydroxyzine were 4, 7 and 14, respectively. After incubation with P-gp inhibitors, these ratios dropped significantly. Loratadine, by contrast, had equivalent transport in both directions and passive permeability was high (24 × 10−6 cm/sec). Dimenhydrinate was the only other sedating antihistamine to exhibit efflux, with a ratio of 10. 4. Gradient conditions of pH (6/7.4) increased efflux of terfenadine and desloratadine to over 31 and 38 fold respectively, yet this increased efflux was not associated with P-gp. 5. Altering functional P-gp in the gut is likely to influence absorption of some sedating antihistamines such as dimenhydrinate and hydroxyzine and most less-sedating antihistamines except loratadine. In addition, desloratadine exhibits pH dependent efflux which could further induce variable absorption of this antihistamine.

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