TY - JOUR
T1 - Transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the amino acid transporter ATB 0,+
AU - Umapathy, Nagavedi S.
AU - Ganapathy, Vadivel
AU - Ganapathy, Malliga E.
N1 - Funding Information:
This work was supported by NIH grants GM65344 (to M. E. G.) and HD44404 (to V. G.).
PY - 2004/7
Y1 - 2004/7
N2 - Purpose. The purpose of this study was to analyze the transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the Na +/Cl --coupled amino acid transporter ATB 0,+. Methods. The interaction of amino acid esters and valganciclovir with the cloned rat ATB 0,+ was evaluated in a mammalian cell expression system and in the Xenopus oocyte expression system. Results. In mammalian cells, expression of ATB 0,+ induced glycine uptake. This uptake was inhibited by valine and its methyl, butyl, and benzyl esters. The benzyl esters of other neutral amino acids were also effective inhibitors. Valganciclovir, the valyl ester of ganciclovir, was also found to inhibit ATB 0,+-mediated glycine uptake competitively. Exposure of ATB 0,+-expressing oocytes to glycine induced inward currents. Exposure to different valyl esters (methyl, butyl, and benzyl), benzyl esters of various neutral amino acids, and valganciclovir also induced inward currents in these oocytes. The current induced by valganciclovir was saturable with a K 0.5 value of 3.1 ± 0.7 mM and was obligatorily dependent on Na + and Cl -. The Na +:Cl -:valganciclovir stoichiometry was 2 or 3:1:1. Conclusions Amino acid esters and the amino-acid-based prodrug valganciclovir are transported by ATB 0,+. This shows that ATB 0,+ can serve as an effective delivery system for amino acid-based prodrugs.
AB - Purpose. The purpose of this study was to analyze the transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the Na +/Cl --coupled amino acid transporter ATB 0,+. Methods. The interaction of amino acid esters and valganciclovir with the cloned rat ATB 0,+ was evaluated in a mammalian cell expression system and in the Xenopus oocyte expression system. Results. In mammalian cells, expression of ATB 0,+ induced glycine uptake. This uptake was inhibited by valine and its methyl, butyl, and benzyl esters. The benzyl esters of other neutral amino acids were also effective inhibitors. Valganciclovir, the valyl ester of ganciclovir, was also found to inhibit ATB 0,+-mediated glycine uptake competitively. Exposure of ATB 0,+-expressing oocytes to glycine induced inward currents. Exposure to different valyl esters (methyl, butyl, and benzyl), benzyl esters of various neutral amino acids, and valganciclovir also induced inward currents in these oocytes. The current induced by valganciclovir was saturable with a K 0.5 value of 3.1 ± 0.7 mM and was obligatorily dependent on Na + and Cl -. The Na +:Cl -:valganciclovir stoichiometry was 2 or 3:1:1. Conclusions Amino acid esters and the amino-acid-based prodrug valganciclovir are transported by ATB 0,+. This shows that ATB 0,+ can serve as an effective delivery system for amino acid-based prodrugs.
KW - amino acid esters
KW - amino acid transporter ATB
KW - drug delivery
KW - valganciclovir
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U2 - 10.1023/B:PHAM.0000033019.49737.28
DO - 10.1023/B:PHAM.0000033019.49737.28
M3 - Article
C2 - 15290873
AN - SCOPUS:3242683504
SN - 0724-8741
VL - 21
SP - 1303
EP - 1310
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 7
ER -