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Research ArticleArticle

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

Stewart T. Dunn, Laura Hedges, Kathleen E. Sampson, Yurong Lai, Sean Mahabir, Larissa Balogh and Charles W. Locuson
Drug Metabolism and Disposition May 2011, 39 (5) 789-795; DOI: https://doi.org/10.1124/dmd.110.034827
Stewart T. Dunn
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Laura Hedges
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Kathleen E. Sampson
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Yurong Lai
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Sean Mahabir
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Larissa Balogh
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Charles W. Locuson
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Abstract

Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 μg/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad. Whereas spinosad pharmacokinetics were unchanged in the presence of ivermectin, ivermectin plasma pharmacokinetics revealed a statistically significant increase in the area under the curve (3.6-fold over the control) when ivermectin was coadministered with spinosad. The majority of the interaction is proposed to result from inhibition of intestinal and/or hepatic P-gp-mediated secretory pathways of ivermectin. Furthermore, in vitro Transwell experiments with a human multidrug resistance 1-transfected Madin-Darby canine kidney II cell line showed polarized efflux at concentrations ≤2 μM, indicating that spinosad is a high-affinity substrate of P-gp. In addition, spinosad was a strong inhibitor of the P-gp transport of digoxin, calcein acetoxymethyl ester (IC50 = 3.2 μM), and ivermectin (IC50 = 2.3 μM). The findings suggest that spinosad, acting as a P-gp inhibitor, increases the risk of ivermectin neurotoxicity by inhibiting secretion of ivermectin to increase systemic drug levels and by inhibiting P-gp at the blood-brain barrier.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034827.

  • ABBREVIATIONS:

    AUC
    area under the curve
    CNS
    central nervous system
    P-gp
    P-glycoprotein
    BBB
    blood-brain barrier
    MEM
    minimal essential medium
    HBSS
    Hanks' balanced salt solution
    calcein AM
    calcein acetoxymethyl ester
    MDCK
    Madin-Darby canine kidney
    MDR
    multidrug resistance
    MDCK-MDR1
    human MDR1 gene-transfected MDCK II
    A
    apical
    B
    basolateral
    ER
    efflux ratio
    CP100356
    N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine.

  • Received June 7, 2010.
  • Accepted February 14, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

Stewart T. Dunn, Laura Hedges, Kathleen E. Sampson, Yurong Lai, Sean Mahabir, Larissa Balogh and Charles W. Locuson
Drug Metabolism and Disposition May 1, 2011, 39 (5) 789-795; DOI: https://doi.org/10.1124/dmd.110.034827

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Research ArticleArticle

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

Stewart T. Dunn, Laura Hedges, Kathleen E. Sampson, Yurong Lai, Sean Mahabir, Larissa Balogh and Charles W. Locuson
Drug Metabolism and Disposition May 1, 2011, 39 (5) 789-795; DOI: https://doi.org/10.1124/dmd.110.034827
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