| Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies. | |
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MedLine Citation:
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PMID: 8957239 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In a comparison paper, we show the azithromycin causes a lysosomal phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal phospholipidosis. |
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Authors:
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J P Montenez; F Van Bambeke; J Piret; A Schanck; R Brasseur; P M Tulkens; M P Mingeot-Leclercq |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: European journal of pharmacology Volume: 314 ISSN: 0014-2999 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 1996 Oct |
Date Detail:
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Created Date: 1997-03-10 Completed Date: 1997-03-10 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: NETHERLANDS |
Other Details:
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Languages: eng Pagination: 215-27 Citation Subset: IM |
Affiliation:
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Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70, Bruxelles, Belgium. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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chemistry* Azithromycin / chemistry* Computer Simulation Drug Interactions Fluorescence Polarization Gentamicins / chemistry Magnetic Resonance Spectroscopy Molecular Conformation Phospholipids / chemistry* |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Gentamicins; 0/Phospholipids; 83905-01-5/Azithromycin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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