Abstract
Purpose. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1510-1518 |
| Number of pages | 9 |
| Journal | Pharmaceutical Research |
| Volume | 22 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Sep 2005 |
| MoE publication type | A1 Journal article-refereed |
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Keywords
- Caco-2 permeability
- Floxuridine prodrugs
- Metabolism
- PEPT1
- Thymidine phosphorylase
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Floxuridine amino acid ester prodrugs : Enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. / Landowski, Christopher P.; Song, Xueqin; Lorenzi, Philip L.; Hilfinger, John M.; Amidon, Gordon L.
In: Pharmaceutical Research, Vol. 22, No. 9, 01.09.2005, p. 1510-1518.Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - Floxuridine amino acid ester prodrugs
T2 - Enhancing Caco-2 permeability and resistance to glycosidic bond metabolism
AU - Landowski, Christopher P.
AU - Song, Xueqin
AU - Lorenzi, Philip L.
AU - Hilfinger, John M.
AU - Amidon, Gordon L.
PY - 2005/9/1
Y1 - 2005/9/1
N2 - Purpose. 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.
AB - Purpose. 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.
KW - Caco-2 permeability
KW - Floxuridine prodrugs
KW - Metabolism
KW - PEPT1
KW - Thymidine phosphorylase
UR - http://www.scopus.com/inward/record.url?scp=24044545862&partnerID=8YFLogxK
U2 - 10.1007/s11095-005-6156-9
DO - 10.1007/s11095-005-6156-9
M3 - Article
C2 - 16132363
AN - SCOPUS:24044545862
VL - 22
SP - 1510
EP - 1518
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 9
ER -