Transport of amino acid-based prodrugs by the Na+- and Cl(-) -coupled amino acid transporter ATB0,+ and expression of the transporter in tissues amenable for drug delivery.
We evaluated the potential of the Na(+)- and Cl(-)-coupled amino acid transporter ATB(0,+) as a delivery system for amino acid-based prodrugs. Immunofluorescence analysis indicated that ATB(0,+) is expressed abundantly on the luminal surface of cells lining the lumen of the large intestine and the airways of the lung and in various ocular tissues, including the conjunctival epithelium, the tissues easily amenable for drug delivery. We screened a variety of beta-carboxyl derivatives of aspartate and gamma-carboxyl derivatives of glutamate as potential substrates for this transporter using heterologous expression systems. In mammalian cells expressing the cloned ATB(0,+), several of the aspartate and glutamate derivatives inhibited glycine transport via ATB(0,+). Direct evidence for ATB(0,+)-mediated transport of these derivatives was obtained in Xenopus laevis oocytes using electrophysiological methods. Exposure of oocytes, which express ATB(0,+) heterologously, to aspartate beta-benzyl ester as a model derivative induced inward currents in a Na(+)- and Cl(-)-dependent manner with a Na(+)/Cl(-)/aspartate beta-benzyl ester stoichiometry of 2:1:1. ATB(0,+) transported not only the beta-carboxyl derivatives of aspartate and the gamma-carboxyl derivatives of glutamate but also valacyclovir, which is an alpha-carboxyl ester of acyclovir with valine. The transport of valacyclovir via ATB(0,+) was demonstrable in both heterologous expression systems. This process was dependent on Na(+) and Cl(-). The ability of ATB(0,+) to transport valacyclovir was comparable with that of the peptide transporter PEPT1. These findings suggest that ATB(0,+) has significant potential as a delivery system for amino acid-based drugs and prodrugs.
Hatanaka
Takahiro
T
Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Haramura
Masayuki
M
Fei
You-Jun
YJ
Miyauchi
Seiji
S
Bridges
Christy C
CC
Ganapathy
Preethi S
PS
Smith
Sylvia B
SB
Ganapathy
Vadivel
V
Ganapathy
Malliga E
ME
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002712:Chlorides / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009865:Oocytes / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014982:Xenopus laevis
D026962:Amino Acid Transport System ASC; D026905:Amino Acid Transport Systems; D000596:Amino Acids; D002712:Chlorides; D015778:Minor Histocompatibility Antigens; D011355:Prodrugs; C420506:SLC1A5 protein, human; C498850:Slc1a5 protein, mouse; D012964:Sodium; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir