| 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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MedLine Citation:
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PMID: 12388672 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 (P(app)) 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 (P(app) <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 microM) in the perfusates fully inhibited the P-gp activity in the BBB and dramatically increased the P(app) values 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 P(app) 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. |
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Authors:
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Weiqing Chen; Jerry Z Yang; Rikke Andersen; Lisbeth H Nielsen; Ronald T Borchardt |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 303 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2002 Nov |
Date Detail:
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Created Date: 2002-10-21 Completed Date: 2002-11-22 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 849-57 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acridines
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pharmacology Algorithms Animals Biotransformation Blood-Brain Barrier / drug effects* Brain Chemistry / drug effects Chromatography, High Pressure Liquid Diazepam / pharmacology Enkephalin, Leucine-2-Alanine / analogs & derivatives, pharmacokinetics* GABA Modulators / pharmacology Isoquinolines / pharmacology Kinetics Male Mass Spectrometry P-Glycoprotein / metabolism Perfusion Prodrugs / pharmacokinetics* Quinidine / pharmacology Rats Rats, Sprague-Dawley Tetrahydroisoquinolines* |
| Grant Support | |
ID/Acronym/Agency:
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DA 09315/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Acridines; 0/GABA Modulators; 0/Isoquinolines; 0/P-Glycoprotein; 0/Prodrugs; 0/Tetrahydroisoquinolines; 143664-11-3/GF 120918; 439-14-5/Diazepam; 56-54-2/Quinidine; 63631-40-3/Enkephalin, Leucine-2-Alanine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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