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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Permeation Characteristics of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs across the Blood-Brain Barrier Using an In Situ Perfused Rat Brain Model

Weiqing Chen, Jerry Z. Yang, Rikke Andersen, Lisbeth H. Nielsen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 849-857; DOI: https://doi.org/10.1124/jpet.102.037143
Weiqing Chen
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Jerry Z. Yang
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Rikke Andersen
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Lisbeth H. Nielsen
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Ronald T. Borchardt
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Abstract

The permeation characteristics of a model opioid peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and its cyclic prodrugs [acyloxyalkoxy-based cyclic prodrug of DADLE (AOA-DADLE), coumarinic acid-based cyclic prodrug of DADLE (CA-DALE), and oxymethyl-modified coumarinic acid-based cyclic prodrug of DADLE (OMCA-DADLE)] across the blood-brain barrier (BBB) were determined using an in situ perfused rat brain model. The rat brains were perfused with Krebs-bicarbonate buffer containing test compounds in the absence or presence of a specific P-glycoprotein inhibitor (GF-120918). Brain samples were collected after perfusion and processed by a capillary depletion method. After liquid phase extraction with acetonitrile, samples were analyzed using high-performance liquid chromatography with tandem mass spectrometric detection. Linear uptake kinetics of DADLE and its cyclic prodrugs was observed within the range of 60 to 240 s of perfusion. The apparent permeability coefficient (Papp) of DADLE across the BBB was very low (<10−7 cm/s), probably due to its unfavorable physicochemical properties (e.g., charge, hydrophilicity, and high hydrogen-bonding potential). All three cyclic prodrugs, however, also exhibited low membrane permeation (Papp <10−7 cm/s) in spite of their more favorable physicochemical properties (e.g., no charge, high hydrophobicity, and low hydrogen-bonding potential). Inclusion of GF-120918 (10 μM) in the perfusates fully inhibited the P-gp activity in the BBB and dramatically increased the Pappvalues of AOA-DADLE, CA-DADLE, and OMCA-DADLE by approximately 50-, 460-, and 170-fold, respectively. In contrast, GF-120918 had no effect on the Papp value of DADLE. In addition, the observed bioconversions of the prodrugs to DADLE in the rat brains after 240-s perfusion were very low (5.1% from AOA-DADLE, 0.6% from CA-DADLE, and 0.2% from OMCA-DADLE), which was consistent with the in vitro bioconversion rates determined previously in rat brain homogenates.

Footnotes

  • This research was supported by Grant DA09315 from the U.S. Public Health Service.

  • DOI: 10.1124/jpet.102.037143

  • Abbreviations:
    BBB
    blood-brain barrier
    DADLE
    [d-Ala2,d-Leu5]-enkephalin
    AOA-DADLE
    acyloxyalkoxy-based cyclic prodrug of [d-Ala2,d-Leu5]-enkephalin
    CA-DADLE
    coumarinic acid-based cyclic prodrug of [d-Ala2,d-Leu5]-enkephalin
    OMCA-DADLE
    oxymethyl-modified coumarinic acid-based cyclic prodrug of [d-Ala2,d-Leu5]-enkephalin
    P-gp
    P-glycoprotein
    LCCA
    left common carotid artery
    LC/MS/MS
    high-performance liquid chromatography with tandem mass spectrometric detection
    HPLC
    high-performance liquid chromatography
    • Received April 9, 2002.
    • Accepted August 2, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Evaluation of the Permeation Characteristics of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs across the Blood-Brain Barrier Using an In Situ Perfused Rat Brain Model
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Permeation Characteristics of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs across the Blood-Brain Barrier Using an In Situ Perfused Rat Brain Model

Weiqing Chen, Jerry Z. Yang, Rikke Andersen, Lisbeth H. Nielsen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 849-857; DOI: https://doi.org/10.1124/jpet.102.037143

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Permeation Characteristics of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs across the Blood-Brain Barrier Using an In Situ Perfused Rat Brain Model

Weiqing Chen, Jerry Z. Yang, Rikke Andersen, Lisbeth H. Nielsen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 849-857; DOI: https://doi.org/10.1124/jpet.102.037143
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