| Design of compounds that increase the absorption of polar molecules. | |
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MedLine Citation:
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PMID: 9342389 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hydrophilic drugs are often poorly absorbed when administered orally. There has been considerable interest in the possibility of using absorption enhancers to promote absorption of polar molecules across membrane surfaces. The bile acids are one of the most widely investigated classes of absorption enhancers, but there is disagreement about what features of bile acid enhancers are responsible for their efficacy. We have designed a class of glycosylated bile acid derivatives to evaluate how increasing the hydrophilicity of the steroid nucleus affects the ability to transport polar molecules across membranes. Some of the glycosylated molecules are significantly more effective than taurocholate in promoting the intestinal absorption of a range of drugs, showing that hydrophobicity is not a critical parameter in transport efficacy, as previously suggested. Furthermore, the most effective glycosylated compound is also far less damaging to membranes than the best bile acid absorption promoters, presumably because it is more hydrophilic. The results reported here show that it is possible to decouple absorption-promoting activity from membrane damage, a finding that should spark interest in the design of new compounds to facilitate the delivery of polar drugs. |
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Authors:
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C L Bowe; L Mokhtarzadeh; P Venkatesan; S Babu; H R Axelrod; M J Sofia; R Kakarla; T Y Chan; J S Kim; H J Lee; G L Amidon; S Y Choe; S Walker; D Kahne |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 94 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 1997 Oct |
Date Detail:
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Created Date: 1997-12-04 Completed Date: 1997-12-04 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 12218-23 Citation Subset: IM; S |
Affiliation:
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Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Transport / drug effects Calcitonin / pharmacokinetics Cholic Acids / pharmacology*, toxicity Drug Design* Female Gentamicins / pharmacokinetics Glycosylation Ileum / metabolism* Insulin / blood, metabolism Intestinal Absorption / drug effects* Pharmaceutical Preparations / metabolism Rats Rats, Sprague-Dawley Vancomycin / pharmacokinetics |
| Chemical | |
Reg. No./Substance:
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0/Cholic Acids; 0/Gentamicins; 0/Pharmaceutical Preparations; 11061-68-0/Insulin; 1404-90-6/Vancomycin; 9007-12-9/Calcitonin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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