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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Jerry Z. Yang, Weiqing Chen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 840-848; DOI: https://doi.org/10.1124/jpet.102.037135
Jerry Z. Yang
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Weiqing Chen
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Ronald T. Borchardt
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Abstract

In vitro stability and in vivo pharmacokinetic studies 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, coumarinic acid-based cyclic prodrug of DADLE, and oxymethyl-modified coumarinic acid-based cyclic prodrug of DADLE) were conducted. The enzymatic stability of DADLE and its prodrugs in various biological media was determined at 37°C in the presence and absence of paraoxon, a known esterase inhibitor. The prodrugs exhibited metabolic stability to exo- and endopeptidases, and esterase-catalyzed bioconversion of the prodrugs to DADLE was observed. For pharmacokinetic studies in rats, various biological samples (blood, bile, urine, and brain) were collected after i.v. administration of DADLE and its prodrugs. The samples were analyzed by high-performance liquid chromatography with tandem mass spectrometric detection, and the conversion from the prodrugs to intermediates to DADLE was monitored. The prodrugs exhibited similar pharmacokinetic properties and showed improved stability compared with DADLE in rat blood. This increased stability led to higher plasma concentrations of DADLE after i.v. administration of the prodrugs compared with i.v. administration of DADLE alone. In terms of elimination pathways, metabolism by endopeptidases was the major route for DADLE elimination, whereas rapid biliary excretion was the major route of elimination for the prodrugs. The rapid elimination of the prodrugs by the liver and the formation of stable intermediates after esterase hydrolysis limited the bioconversion efficiencies of the prodrugs to DADLE after i.v. administration. The substrate activity of the prodrugs for efflux transporters (e.g., P-glycoprotein) in the blood-brain barrier significantly restricted their access to the brain.

Footnotes

  • This research was supported by a grant from the U.S. Public Health Service (DA09315).

  • DOI: 10.1124/jpet.102.037135

  • Abbreviations:
    BBB
    blood-brain barrier
    P-gp
    P-glycoprotein
    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
    PNPB
    p-nitrophenyl butyrate
    DMSO
    dimethyl sulfoxide
    PEG300
    polyethylene glycol (ave. mol. wt. 300)
    HBSS
    Hanks' balanced salt solution
    HPLC
    high-performance liquid chromatography
    LC/MS/MS
    high-performance liquid chromatography with tandem mass spectrometric detection
    SPE
    solid phase extraction
    AUC
    area under the curve
    • 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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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Jerry Z. Yang, Weiqing Chen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 840-848; DOI: https://doi.org/10.1124/jpet.102.037135

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Stability and In Vivo Pharmacokinetic Studies of a Model Opioid Peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and Its Cyclic Prodrugs

Jerry Z. Yang, Weiqing Chen and Ronald T. Borchardt
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 840-848; DOI: https://doi.org/10.1124/jpet.102.037135
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