Pharmacodynamic and pharmacokinetic characterization of poly(ethylene glycol) conjugation to met-enkephalin analog [D-Pen2,D-Pen5]-enkephalin (DPDPE)

Ken A. Witt, Jason D. Huber, Richard D. Egleton, Michael J. Roberts, Michael D. Bentley, Lihong Guo, Hongbing Wei, Henry I. Yamamura, Thomas P. Davis

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48 Scopus citations


Poly(ethylene glycol), or PEG, conjugation to proteins and peptides is a growing technology used to enhance efficacy of therapeutics. This investigation assesses pharmacodynamic and pharmacokinetic characteristics of PEG-conjugated [D-Pen2,D-Pen5]-enkephalin (DPDPE), a met-enkephalin analog, in rodent (in vivo, in situ) and bovine (in vitro) systems. PEG-DPDPE showed increased analgesia (i.v.) compared with nonconjugated form (p < 0.01), despite a 172-fold lower binding affinity for the δ-opioid receptor. [125]PEG-DPDPE had a 36-fold greater hydrophilicity (p < 0.01) and 12% increase in the unbound plasma protein fraction (p < 0.01), compared with [125]DPDPE. [125]PEG-DPDPE had a 2.5-fold increase in elimination half-life (p < 0.01), 2.7-fold decrease in volume of distribution (p < 0.01), and a 7-fold decrease in plasma clearance rate (p < 0.01) to [125]DPDPE. Time course distribution showed significant concentration differences (p < 0.01) in plasma, whole blood, liver, gallbladder, gastrointestinal (GI) content, GI tract, kidneys, spleen, urine, and brain (brain, p < 0.05), between the conjugated and nonconjugated forms. Increased brain uptake of [125]PEG-DPDPE corresponded to analgesia data. [125]PEG-DPDPE in brain was shown to be 58.9% intact, with 41.1% existing as [125]DPDPE (metabolite), whereas [125l]DPDPE was 25.7% intact in the brain (at 30 min). In vitro P-glycoprotein affinity was shown for [125]DPDPE (p < 0.01) but not shown for [125l]PEG-DPDPE. In vitro saturable uptake, with 100 μM DPDPE, was shown for [125l]PEG-DPDPE (p < 0.05). In this study, PEG-conjugated DPDPE seems to act as a prodrug, enhancing peripheral pharmacokinetics, while undergoing hydrolysis in the brain and allowing nonconjugated DPDPE to act at the receptor.

Original languageEnglish (US)
Pages (from-to)848-856
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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