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Propylene glycol-Linked Amino Acid/Dipeptide Diester Prodrugs of Oleanolic Acid for PepT1-Mediated Transport: Synthesis, Intestinal Permeability and Pharmacokinetics.
MedLine Citation:
PMID:  23339520     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
In our previous studies, ethylene glycol-linked amino acid diester prodrugs of Oleanolic Acid (OA), a Biopharmaceutics Classification System (BCS) Class Ⅳ drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (Peff) of the prodrugs. Peff of 7a, 7b, 7c, 9a, 9b, 9c, 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, 1.4-fold, respectively) in 2-(N-Morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p<0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH7.4, except for 7c, 9a, 9d, Peff of the other prodrugs comtaining 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), 9c (1.7-fold), exhibited significantly higher than that of OA (p<0.01). Inhibition studies with Glycyl-Sarcosine (Gly-Sar, a typical substrate of PepT1), turned out that Peff of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced (p<0.01). Compared to the apparent permeability coefficient (Papp) of OA with Caco-2 cell monolayer, significant enhancement of the Papp of 7a(5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), 9d (1.39-fold) was also observed (p<0.01). Inhibition studies with Gly-Sar (1 mM) showed that Papp of 7a, 9b, 9c significantly reduced by 1.3-fold, 1.6-fold and 1.4-fold (p<0.01), respectively. These results may be attributed to PepT1-mediated transport and their differential affinity toward PepT1. According to the permeability and affinity, 7a and 9b were selected in the pharmacokinetic studies in rats. Compared with group OA, Cmax for group 7a and 9b was enhanced to 3.04-fold (p<0.01) and 2.62-fold (p<0.01), respectively. AUC0→24 was improved to 3.55-fold (p<0.01) and 3.39-fold (p<0.01), respectively. Compared to the ethylene glycol-linked amino acid diester prodrugs of OA in our previous work, results from this study revealed that part of the propylene glycol-linked amino acid/dipeptide diester prodrugs showed better stability, permeability, affinity and bioavailability. In conclusion, propylene glycol-linked amino acid/dipeptide diester prodrugs of OA may be suitable for PepT1-targeted prodrugs of OA to improve the oral bioavailability of OA.
Authors:
Feng Cao; Yahan Gao; Meng Wang; Lei Fang; Qineng Ping
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-22
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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