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

Takahiro Hatanaka, Masayuki Haramura, You Jun Fei, Seiji Miyauchi, Christy C. Bridges, Preethi S. Ganapathy, Sylvia B Smith, Vadivel Ganapathy, Malliga E. Ganapathy

Research output: Contribution to journalArticle

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Abstract

We evaluated the potential of the Na+- and Cl --coupled amino acid transporter ATB0,+ as a delivery system for amino acid-based prodrugs. Immunofluorescence analysis indicated that ATB0,+ 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 β-carboxyl derivatives of aspartate and γ-carboxyl derivatives of glutamate as potential substrates for this transporter using heterologous expression systems. In mammalian cells expressing the cloned ATB0,+, several of the aspartate and glutamate derivatives inhibited glycine transport via ATB 0,+. Direct evidence for ATB0,+-mediated transport of these derivatives was obtained in Xenopus laevis oocytes using electrophysiological methods. Exposure of oocytes, which express ATB 0,+ heterologously, to aspartate β-benzyl ester as a model derivative induced inward currents in a Na+- and Cl --dependent manner with a Na+/Cl-/aspartate β-benzyl ester stoichiometry of 2:1:1. ATB0,+ transported not only the β-carboxyl derivatives of aspartate and the γ-carboxyl derivatives of glutamate but also valacyclovir, which is an α-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 ATB0,+ to transport valacyclovir was comparable with that of the peptide transporter PEPT1. These findings suggest that ATB0,+ has significant potential as a delivery system for amino acid-based drugs and prodrugs.

Original languageEnglish (US)
Pages (from-to)1138-1147
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume308
Issue number3
DOIs
StatePublished - Mar 1 2004

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valacyclovir
Amino Acid Transport Systems
Prodrugs
Aspartic Acid
Amino Acids
Glutamic Acid
Esters
Pharmaceutical Preparations
Oocytes
Acyclovir
Large Intestine
Xenopus laevis
Valine
Glycine
Fluorescent Antibody Technique
Epithelium
Lung

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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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. / Hatanaka, Takahiro; Haramura, Masayuki; Fei, You Jun; Miyauchi, Seiji; Bridges, Christy C.; Ganapathy, Preethi S.; Smith, Sylvia B; Ganapathy, Vadivel; Ganapathy, Malliga E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 308, No. 3, 01.03.2004, p. 1138-1147.

Research output: Contribution to journalArticle

Hatanaka, Takahiro ; Haramura, Masayuki ; Fei, You Jun ; Miyauchi, Seiji ; Bridges, Christy C. ; Ganapathy, Preethi S. ; Smith, Sylvia B ; Ganapathy, Vadivel ; Ganapathy, Malliga E. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2004 ; Vol. 308, No. 3. pp. 1138-1147.
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abstract = "We evaluated the potential of the Na+- and Cl --coupled amino acid transporter ATB0,+ as a delivery system for amino acid-based prodrugs. Immunofluorescence analysis indicated that ATB0,+ 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 β-carboxyl derivatives of aspartate and γ-carboxyl derivatives of glutamate as potential substrates for this transporter using heterologous expression systems. In mammalian cells expressing the cloned ATB0,+, several of the aspartate and glutamate derivatives inhibited glycine transport via ATB 0,+. Direct evidence for ATB0,+-mediated transport of these derivatives was obtained in Xenopus laevis oocytes using electrophysiological methods. Exposure of oocytes, which express ATB 0,+ heterologously, to aspartate β-benzyl ester as a model derivative induced inward currents in a Na+- and Cl --dependent manner with a Na+/Cl-/aspartate β-benzyl ester stoichiometry of 2:1:1. ATB0,+ transported not only the β-carboxyl derivatives of aspartate and the γ-carboxyl derivatives of glutamate but also valacyclovir, which is an α-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 ATB0,+ to transport valacyclovir was comparable with that of the peptide transporter PEPT1. These findings suggest that ATB0,+ has significant potential as a delivery system for amino acid-based drugs and prodrugs.",
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AU - Bridges, Christy C.

AU - Ganapathy, Preethi S.

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AU - Ganapathy, Malliga E.

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