| Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir. | |
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MedLine Citation:
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PMID: 11288106 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate beta-ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37 degrees C. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37 degrees C. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate beta-ester. The stability of all three esters decreased with increasing pH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p < 1%). L-Aspartate beta-ester was absorbed to the extent of approximately 8% over 90 min of perfusion at an initial drug concentration of 100 microM. Nasal absorption of L-aspartate beta-ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate beta-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system. |
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Authors:
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C Yang; H Gao; A K Mitra |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of pharmaceutical sciences Volume: 90 ISSN: 0022-3549 ISO Abbreviation: J Pharm Sci Publication Date: 2001 May |
Date Detail:
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Created Date: 2001-04-05 Completed Date: 2001-07-19 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985195R Medline TA: J Pharm Sci Country: United States |
Other Details:
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Languages: eng Pagination: 617-24 Citation Subset: IM |
Copyright Information:
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Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association. |
Affiliation:
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Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, 5005 Rockhill Road, Kansas City, Missouri 64110, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acyclovir
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chemistry,
pharmacokinetics* Administration, Intranasal Animals Antiviral Agents / chemistry, pharmacokinetics* Aspartic Acid / pharmacokinetics* Drug Stability Male Nasal Mucosa / metabolism* Prodrugs / chemistry, pharmacokinetics* Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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2R01 EY 09171-06/EY/NEI NIH HHS; 2R01 EY10659-05/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/Prodrugs; 56-84-8/Aspartic Acid; 59277-89-3/Acyclovir |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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