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R. vaishya, R. Talluri, R. Gaudana, S. Samanta, A. Mitra; Synthesis and Evaluation of Metabolism and Cellular Permeability of Enzymatically Stable Dipeptide Prodrugs of Acyclovir. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5128.
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To design and evaluate novel enzymatically stable dipeptide prodrugs as potential candidates to improve the oral absorption of acyclovir.
L-Valine-L-Valine-acyclovir (LLACV), L-Valine-D-Valine-acyclovir (LDACV), D-Valine-L-Valine-acyclovir (DLACV) and D-Valine-D-Valine-acyclovir (DDACV) were synthesized in our laboratory. Uptake and transport studies were conducted using Human colonic adenocarcinoma cells (Caco-2). Buffer stability studies were performed at different pH using Dulbecco’s Phosphate Buffered Saline (DPBS). Metabolism of these drugs was studied in various matrices like Caco-2, rat intestine and liver homogenates.
All the compounds were confirmed using LC-MS/MS and NMR spectroscopy. Uptake and transport of [3H] glycyl-sarcosine was inhibited by all prodrugs except DDACV. DLACV and DDACV did not show any degradation in Caco-2 homogenate. Excluding DDACV all the prodrugs were hydrolyzed in rat intestine and liver homogenates during the time period of study. The order of permeability across Caco-2 was LDACV>LLACV>DDACV>DLACV. There was a good correlation between the amount of prodrug transported and over all permeability across Caco-2.
Incorporation of one D-Valine at a definite position into a dipeptide did not abolish its affinity towards peptide transporter (PEPT). More over it enhanced their enzymatic stability depending on the position in a dipeptide conjugate (N-terminus or Carboxyl terminus). This technology improved both the cellular permeability as well as the amount of intact prodrug transported. This enhanced prodrug transport would enable targeting the nutrient transporters at blood ocular barriers (BOB) in order to improve ocular bioavailability of acyclovir after oral administration.
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