Document Detail


Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.
MedLine Citation:
PMID:  19957998     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. l-Valine, l-isoleucine, and l-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC(50): 0.65 and 0.63 mM, respectively), and all three l-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the l-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good substrates of hVACVase (k(cat)/K(m) in mM(-1) x s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.
Authors:
Jing Sun; Arik Dahan; Gordon L Amidon
Related Documents :
7355008 - Bile acid excretion and patterns of fatty acid absorption in formula-fed premature infa...
11732748 - Ursodeoxycholic acid action on the transport function of the small intestine in normal ...
8932438 - Water-in-oil microemulsions containing medium-chain fatty acids/salts: formulation and ...
11920758 - Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium l...
1663578 - Signal transduction by the human thyrotropin receptor: studies on the role of individua...
16642728 - Schisandra chinensis protects against adriamycin-induced cardiotoxicity in rats.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-21     Completed Date:  2010-03-02     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  624-32     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry
Antiviral Agents / chemical synthesis*,  pharmacokinetics
Caco-2 Cells
Carboxylic Ester Hydrolases / metabolism
Drug Delivery Systems / methods*
Esters / chemistry
Guanidines / chemical synthesis,  pharmacokinetics*
HeLa Cells
Humans
Intestinal Absorption*
Kinetics
Prodrugs / pharmacokinetics*
Symporters / metabolism
Grant Support
ID/Acronym/Agency:
R01 GM037188/GM/NIGMS NIH HHS; R01 GM037188-23/GM/NIGMS NIH HHS; U01AI061457/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Antiviral Agents; 0/Esters; 0/Guanidines; 0/Prodrugs; 0/SLC15A1 protein, human; 0/Symporters; 2002-16-6/phenylguanidine; EC 3.1.1.-/BPHL protein, human; EC 3.1.1.-/Carboxylic Ester Hydrolases
Comments/Corrections

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


Previous Document:  Non-Steady State Modeling of Arsenic Diagenesis in Lake Sediments.
Next Document:  Modular Synthesis and in Vitro and in Vivo Antimalarial Assessment of C-10 Pyrrole Mannich Base Deri...