Document Detail

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells.
MedLine Citation:
PMID:  16805952     Owner:  NLM     Status:  MEDLINE    
This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of L-valyl-ara-C, a peptidomimetic prodrug of ara-C (cytarabine). After the synthesis of L-valyl-ara-C via the incorporation of L-valine into the N4-amino group of the cytosine ring in araC, the gastrointestinal stability of L-valyl-ara-C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of L-valyl-ara-C were also examined in Caco-2 cells. The disappearance half-life of L-valyl-ara-C was 2.2 h in artificial gastric juice, while the degradation of L-valyl-ara-C was negligible in artificial intestinal fluid and also in the supernatant above the Caco-2 cell monolayer during the 2-h incubation. The cellular accumulation of L-valyl-ara-C was 5-fold higher than that of ara-C in Caco-2 cells. Furthermore, the cellular uptake of L-valyl-ara-C did not increase proportionally to the increase in drug concentration. The cellular accumulation of L-valyl-ara-C was significantly reduced in the presence of uridine, p-aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of L-valine and benzoic acid, suggesting that L-valyl-ara-C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, L-valyl-ara-C could be effective to improve the oral absorption of ara-C via the carrier-mediated transport pathway.
Eun-Pa Cheon; Joon Hee Hong; Hyo-Kyung Han
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  58     ISSN:  0022-3573     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-29     Completed Date:  2006-12-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  927-32     Citation Subset:  IM    
College of Pharmacy, Chosun University, 375 Seosuk-dong, Gwangju, Korea.
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MeSH Terms
Biological Transport
Caco-2 Cells
Chromatography, High Pressure Liquid
Cytarabine / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacokinetics
Drug Stability
Gastric Juice / chemistry
Intestinal Secretions / chemistry
Intestines / metabolism
Peptides / chemistry*
Prodrugs / chemical synthesis,  chemistry,  pharmacokinetics*
Reg. No./Substance:
0/L-valyl-ara-C; 0/Peptides; 0/Prodrugs; 147-94-4/Cytarabine

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