File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Effect of structural modification of α-aminoxy peptides on their intestinal absorption and transport mechanism

TitleEffect of structural modification of α-aminoxy peptides on their intestinal absorption and transport mechanism
Authors
KeywordsStructural modification
Absorption
Transport mechanism
α-aminoxy peptides
Issue Date2011
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/mpohbp/index.html
Citation
Molecular Pharmaceutics, 2011, v. 8 n. 4, p. 1073-1082 How to Cite?
AbstractA representative α-aminoxy peptide 1 has been demonstrated to have a potential for the treatment of human diseases associated with Cl - channel dysfunctions. However, its poor intestinal absorption was determined. The purpose of this study was to delineate the transport mechanism responsible for its poor absorption and also to prepare peptide analogues by structural modifications of 1 at its isobutyl side chains without changing the α-aminoxy core for retaining biological activity to improve the intestinal absorption. The poor intestinal absorption of 1 was proved to be due to the P-glycoprotein (P-gp) mediated efflux transport in Caco-2 cell monolayer, intestinal segments in Ussing chamber and rat single pass intestinal perfusion models. Four analogues with propionic acid (2), butanamine (3), methyl (4) and hydroxymethyl side chains (5) were synthesized and tested using the same models. Except for the permeability of 2, the absorbable permeability of the modified peptides in Caco-2 cell monolayer and their intestinal absorption in rats were significantly improved to 7-fold (3), 4-fold (4), 11-fold (5) and 36-fold (2), 42-fold (3), 55-fold (4), 102-fold (5), respectively, compared with 1 (P app, 0.034 ± 0.003 × 10 -6 cm/s; P blood, 1.61 ± 0.807 × 10 -6 cm/s). More interestingly, the structural modification remarkably altered transport mechanism of the peptides, leading to the conversion of the active transport via P-gp mediation (1, 2), to MRP mediation (3), MRP plus BCRP mediation (4) or a passive diffusion (5). Furthermore, P-gp mediated efflux transport of 1 and 2 was demonstrated to not alter the P-gp expression, while 1 but not 2 exhibited uncompetitive inhibitory effect on P-gp ATPase. The results demonstrated that intestinal absorption and transport mechanism of the α-aminoxy peptides varied significantly with different structures, and their absorption can be dramatically improved by structural modifications, which allow us to further design and prepare better α-aminoxy peptide candidates with appropriate pharmacokinetic fates, including intestinal absorption, for potential clinical use. © 2011 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/139022
ISSN
2015 Impact Factor: 4.342
2015 SCImago Journal Rankings: 1.681
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMa, Ben_HK
dc.contributor.authorZha, Hen_HK
dc.contributor.authorLi, Nen_HK
dc.contributor.authorYang, Den_HK
dc.contributor.authorLin, Gen_HK
dc.date.accessioned2011-09-23T05:44:11Z-
dc.date.available2011-09-23T05:44:11Z-
dc.date.issued2011en_HK
dc.identifier.citationMolecular Pharmaceutics, 2011, v. 8 n. 4, p. 1073-1082en_HK
dc.identifier.issn1543-8384en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139022-
dc.description.abstractA representative α-aminoxy peptide 1 has been demonstrated to have a potential for the treatment of human diseases associated with Cl - channel dysfunctions. However, its poor intestinal absorption was determined. The purpose of this study was to delineate the transport mechanism responsible for its poor absorption and also to prepare peptide analogues by structural modifications of 1 at its isobutyl side chains without changing the α-aminoxy core for retaining biological activity to improve the intestinal absorption. The poor intestinal absorption of 1 was proved to be due to the P-glycoprotein (P-gp) mediated efflux transport in Caco-2 cell monolayer, intestinal segments in Ussing chamber and rat single pass intestinal perfusion models. Four analogues with propionic acid (2), butanamine (3), methyl (4) and hydroxymethyl side chains (5) were synthesized and tested using the same models. Except for the permeability of 2, the absorbable permeability of the modified peptides in Caco-2 cell monolayer and their intestinal absorption in rats were significantly improved to 7-fold (3), 4-fold (4), 11-fold (5) and 36-fold (2), 42-fold (3), 55-fold (4), 102-fold (5), respectively, compared with 1 (P app, 0.034 ± 0.003 × 10 -6 cm/s; P blood, 1.61 ± 0.807 × 10 -6 cm/s). More interestingly, the structural modification remarkably altered transport mechanism of the peptides, leading to the conversion of the active transport via P-gp mediation (1, 2), to MRP mediation (3), MRP plus BCRP mediation (4) or a passive diffusion (5). Furthermore, P-gp mediated efflux transport of 1 and 2 was demonstrated to not alter the P-gp expression, while 1 but not 2 exhibited uncompetitive inhibitory effect on P-gp ATPase. The results demonstrated that intestinal absorption and transport mechanism of the α-aminoxy peptides varied significantly with different structures, and their absorption can be dramatically improved by structural modifications, which allow us to further design and prepare better α-aminoxy peptide candidates with appropriate pharmacokinetic fates, including intestinal absorption, for potential clinical use. © 2011 American Chemical Society.en_HK
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/mpohbp/index.htmlen_HK
dc.relation.ispartofMolecular Pharmaceuticsen_HK
dc.subjectStructural modification-
dc.subjectAbsorption-
dc.subjectTransport mechanism-
dc.subjectα-aminoxy peptides-
dc.titleEffect of structural modification of α-aminoxy peptides on their intestinal absorption and transport mechanismen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1543-8384&volume=8&spage=1073&epage=1082&date=2011&atitle=Effect+of+Structural+Modification+of+alpha-Aminoxy+Peptides+on+Their+Intestinal+Absorption+and+Transport+Mechanismen_US
dc.identifier.emailYang, D:yangdan@hku.hken_HK
dc.identifier.authorityYang, D=rp00825en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/mp1003866en_HK
dc.identifier.pmid21630669-
dc.identifier.scopuseid_2-s2.0-79961056417en_HK
dc.identifier.hkuros196047en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79961056417&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume8en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1073en_HK
dc.identifier.epage1082en_HK
dc.identifier.isiWOS:000293307400010-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridMa, B=51864116400en_HK
dc.identifier.scopusauthoridZha, H=47961579800en_HK
dc.identifier.scopusauthoridLi, N=36065390000en_HK
dc.identifier.scopusauthoridYang, D=7404800756en_HK
dc.identifier.scopusauthoridLin, G=26643369300en_HK

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats