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Research ArticleArticle

Neotrofin Is Transported Out of Brain by a Saturable Mechanism: Possible Involvement of Multidrug Resistance and Monocarboxylic Acid Transporters

Rongzi Yan and Eve M. Taylor
Drug Metabolism and Disposition May 2002, 30 (5) 513-518; DOI: https://doi.org/10.1124/dmd.30.5.513
Rongzi Yan
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Eve M. Taylor
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Abstract

Neotrofin (AIT-082; leteprinim potassium) is transported out of brain by a saturable mechanism and in this study the mechanisms mediating this efflux were evaluated. Intracerebroventricular coadministration of [14C]Neotrofin with verapamil, a P-glycoprotein inhibitor, probenecid, an organic anion transporter inhibitor, 3-[{3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl}-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), a multidrug resistance-associated protein inhibitor, and salicylate or benzoate, both monocarboxylic acid transporter substrates, inhibited the efflux of [14C]Neotrofin. Additionally, Neotrofin inhibited the efflux of [3H]quinidine from brain. Compounds can diffuse from cerebrospinal fluid (CSF) into extracellular fluid of brain parenchyma and thus, efflux of [14C]Neotrofin after intracerebroventricular administration may indicate active transport across choroid plexus epithelium, brain capillary endothelium, or both. To determine whether [14C]Neotrofin efflux occurs at the brain capillary endothelium, experiments were performed in which [14C]Neotrofin was administered intraparenchymally. Thet1/2 for [14C]Neotrofin disappearance from brain after intraparenchymal administration was significantly lower than that for [3H]sucrose and the efflux of Neotrofin was inhibited by 600-fold excess of unlabeled Neotrofin, verapamil, MK571, and salicylate. Together, these data suggest that a saturable mechanism for the efflux of Neotrofin is located at the blood-brain barrier and possibly the blood-CSF barrier. It is likely that multiple transporters are involved in the efflux of Neotrofin and these may include multidrug resistance and monocarboxylic acid transporters. These data are discussed in detail with respect to the site of transporter expression, the recent identification of numerous multidrug resistance-associated protein and monocarboxylic acid transporter homologs, the existence of other potential brain efflux transporters, and the availability of specific pharmacological agents with which to distinguish these transporters.

Footnotes

  • This work was supported by NeoTherapeutics, Inc. (Irvine, CA).

  • Abbreviations used are::
    CNS
    central nervous system
    P-gp
    P-glycoprotein
    MRP
    multidrug resistance-associated protein
    CSF
    cerebrospinal fluid
    TKO
    triple knockout
    DKO
    double knockout
    MCT
    monocarboxylic acid transporter
    OAT
    organic anion transporter
    PBS
    phosphate-buffered saline
    i.p.c.
    intraparenchymal
    ANOVA
    analysis of variance
    MK571
    3-[{3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl}-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
    AIT-082
    Neotrofin
    • Received January 2, 2002.
    • Accepted January 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (5)
Drug Metabolism and Disposition
Vol. 30, Issue 5
1 May 2002
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Research ArticleArticle

Neotrofin Is Transported Out of Brain by a Saturable Mechanism: Possible Involvement of Multidrug Resistance and Monocarboxylic Acid Transporters

Rongzi Yan and Eve M. Taylor
Drug Metabolism and Disposition May 1, 2002, 30 (5) 513-518; DOI: https://doi.org/10.1124/dmd.30.5.513

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Research ArticleArticle

Neotrofin Is Transported Out of Brain by a Saturable Mechanism: Possible Involvement of Multidrug Resistance and Monocarboxylic Acid Transporters

Rongzi Yan and Eve M. Taylor
Drug Metabolism and Disposition May 1, 2002, 30 (5) 513-518; DOI: https://doi.org/10.1124/dmd.30.5.513
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