Floxuridine amino acid ester prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism.
OBJECTIVE
The aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2'-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.


METHODS
Amino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-L: -sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers.


RESULTS
Isoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5'-L: -isoleucyl and 5'-L: -valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5'-L: -isoleucyl and 5'-L: -valyl prodrugs was 8- to 11-fold greater compared with floxuridine.


CONCLUSIONS
Amino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.
Landowski
Christopher P
CP
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Song
Xueqin
X
Lorenzi
Philip L
PL
Hilfinger
John M
JM
Amidon
Gordon L
GL
D000596:Amino Acids / Q000737:chemistry*; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004951:Esterification; D005467:Floxuridine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006027:Glycosides / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000378:metabolism
D000596:Amino Acids; D006027:Glycosides; D011355:Prodrugs; D005467:Floxuridine; D013939:Thymidine Phosphorylase