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    The interactions of P-glycoprotein with antimalarial drugs, including substrate affinity, inhibition and regulation

    240054_240054.pdf (476.3Kb)
    Access Status
    Open access
    Authors
    Senarathna, S.
    Page-Sharp, Madhu
    Crowe, A.
    Date
    2016
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Senarathna, S. and Page-Sharp, M. and Crowe, A. 2016. The interactions of P-glycoprotein with antimalarial drugs, including substrate affinity, inhibition and regulation. PLoS One. 11 (4): pp. 1-17.
    Source Title
    PLoS One
    DOI
    10.1371/journal.pone.0152677
    School
    School of Pharmacy
    Remarks

    This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by/4.0/

    URI
    http://hdl.handle.net/20.500.11937/20971
    Collection
    • Curtin Research Publications
    Abstract

    © 2016 Senarathna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 × 10-6 cm/sec, followed by amodiaquine around 20 × 10-6 cm/sec; both mefloquine and artesunate were around 10 × 10-6 cm/sec. Methylene blue was between 2 and 6 × 10-6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine.

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