Document Detail

Design of compounds that increase the absorption of polar molecules.
MedLine Citation:
PMID:  9342389     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
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:
Created Date:  1997-12-04     Completed Date:  1997-12-04     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  12218-23     Citation Subset:  IM; S    
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
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MeSH Terms
Biological Transport / drug effects
Calcitonin / pharmacokinetics
Cholic Acids / pharmacology*,  toxicity
Drug Design*
Gentamicins / pharmacokinetics
Ileum / metabolism*
Insulin / blood,  metabolism
Intestinal Absorption / drug effects*
Pharmaceutical Preparations / metabolism
Rats, Sprague-Dawley
Vancomycin / pharmacokinetics
Reg. No./Substance:
0/Cholic Acids; 0/Gentamicins; 0/Pharmaceutical Preparations; 11061-68-0/Insulin; 1404-90-6/Vancomycin; 9007-12-9/Calcitonin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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