Design of Compounds that Increase the Absorption of Polar Molecules

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-10, Vol.94 (22), p.12218-12223
Main Authors: Bowe, C L, Mokhtarzadeh, L, Venkatesan, P, Babu, S, Axelrod, H R, Sofia, M J, Kakarla, R, Chan, T Y, Kim, J S, Lee, H J, Amidon, G L, Choe, S Y, Walker, S, Kahne, D
Format: Article
Language:English
Subjects:
Acids
Animals
Bile acids
Biological Sciences
Biological Transport - drug effects
Calcitonin - pharmacokinetics
Cell membranes
Cholic Acids - pharmacology
Cholic Acids - toxicity
Drug Design
Drugs
Erythrocytes
Female
Gentamicins - pharmacokinetics
Glycosylation
Hydrophobicity
Hydroxyls
Ileum - metabolism
Insulin
Insulin - blood
Insulin - metabolism
Intestinal Absorption - drug effects
Molecules
P branes
Pharmaceutical Preparations - metabolism
Pharmacology
Rats
Rats, Sprague-Dawley
Sodium
Steroids
Vancomycin - pharmacokinetics
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.22.12218