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Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium.
Curr Eye Res 2004 Aug-Sep; 29(2-3):153-66CE

Abstract

PURPOSE

The aim of this study was to explore the feasibility of improvement of ocular bioavailability of the antiviral agent acyclovir by designing amino acid prodrugs targeted to the amino acid transporters on the rabbit cornea.

MATERIALS AND METHODS

Transcorneal flux of two water-soluble amino acid ester prodrugs of acyclovir (ACV), gamma-glutamate-ACV (EACV) and L-tyrosine-ACV (YACV), was studied across freshly excised rabbit cornea. Chemical and enzymatic hydrolysis studies of the two prodrugs were also conducted.

RESULTS

EACV inhibited the uptake of [(3)H]L-Arg in rabbit primary corneal epithelial cells (rPCECs). The compound also exhibited longer half-life (t(1/2)) in cornea in comparison to YACV. Transcorneal flux of EACV was observed to be concentration-, energy-, and sodium-dependent and independent of pH within the range studied. EACV transport was inhibited by neutral and cationic amino acids, L-ornithine (specific for cationic amino acids), and BCH (2-aminobicyclo-[2,2,1]-heptane-2-carboxylic-acid) (specific inhibitor for L-type system and B(0,+) system). On the other hand, YACV was not recognized by this amino acid transporter as it failed to inhibit the uptake of [(3)H]Arg, and also its transport across cornea was not inhibited by arginine. YACV and EACV exhibited excellent antiviral activity against HSV-1 and 2 and Varicella-Zoster Virus (VZV) in comparison to ACV.

CONCLUSIONS

Analyses of the inhibition pattern of EACV transport suggests the involvement of a single transport system; namely, B(0,+). Design of amino acid prodrugs seems to be an attractive strategy to enhance the solubility of the otherwise poorly aqueous soluble compounds and also to afford a targeted and possibly enhanced delivery of the active drug.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15512962

Citation

Anand, Banmeet S., et al. "Amino Acid Prodrugs of Acyclovir as Possible Antiviral Agents Against Ocular HSV-1 Infections: Interactions With the Neutral and Cationic Amino Acid Transporter On the Corneal Epithelium." Current Eye Research, vol. 29, no. 2-3, 2004, pp. 153-66.
Anand BS, Katragadda S, Nashed YE, et al. Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium. Curr Eye Res. 2004;29(2-3):153-66.
Anand, B. S., Katragadda, S., Nashed, Y. E., & Mitra, A. K. (2004). Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium. Current Eye Research, 29(2-3), pp. 153-66.
Anand BS, et al. Amino Acid Prodrugs of Acyclovir as Possible Antiviral Agents Against Ocular HSV-1 Infections: Interactions With the Neutral and Cationic Amino Acid Transporter On the Corneal Epithelium. Curr Eye Res. 2004;29(2-3):153-66. PubMed PMID: 15512962.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium. AU - Anand,Banmeet S, AU - Katragadda,Suresh, AU - Nashed,Yasser E, AU - Mitra,Ashim K, PY - 2004/10/30/pubmed PY - 2005/1/14/medline PY - 2004/10/30/entrez SP - 153 EP - 66 JF - Current eye research JO - Curr. Eye Res. VL - 29 IS - 2-3 N2 - PURPOSE: The aim of this study was to explore the feasibility of improvement of ocular bioavailability of the antiviral agent acyclovir by designing amino acid prodrugs targeted to the amino acid transporters on the rabbit cornea. MATERIALS AND METHODS: Transcorneal flux of two water-soluble amino acid ester prodrugs of acyclovir (ACV), gamma-glutamate-ACV (EACV) and L-tyrosine-ACV (YACV), was studied across freshly excised rabbit cornea. Chemical and enzymatic hydrolysis studies of the two prodrugs were also conducted. RESULTS: EACV inhibited the uptake of [(3)H]L-Arg in rabbit primary corneal epithelial cells (rPCECs). The compound also exhibited longer half-life (t(1/2)) in cornea in comparison to YACV. Transcorneal flux of EACV was observed to be concentration-, energy-, and sodium-dependent and independent of pH within the range studied. EACV transport was inhibited by neutral and cationic amino acids, L-ornithine (specific for cationic amino acids), and BCH (2-aminobicyclo-[2,2,1]-heptane-2-carboxylic-acid) (specific inhibitor for L-type system and B(0,+) system). On the other hand, YACV was not recognized by this amino acid transporter as it failed to inhibit the uptake of [(3)H]Arg, and also its transport across cornea was not inhibited by arginine. YACV and EACV exhibited excellent antiviral activity against HSV-1 and 2 and Varicella-Zoster Virus (VZV) in comparison to ACV. CONCLUSIONS: Analyses of the inhibition pattern of EACV transport suggests the involvement of a single transport system; namely, B(0,+). Design of amino acid prodrugs seems to be an attractive strategy to enhance the solubility of the otherwise poorly aqueous soluble compounds and also to afford a targeted and possibly enhanced delivery of the active drug. SN - 0271-3683 UR - https://www.unboundmedicine.com/medline/citation/15512962/Amino_acid_prodrugs_of_acyclovir_as_possible_antiviral_agents_against_ocular_HSV_1_infections:_interactions_with_the_neutral_and_cationic_amino_acid_transporter_on_the_corneal_epithelium_ L2 - http://www.tandfonline.com/doi/full/10.1080/02713680490504614 DB - PRIME DP - Unbound Medicine ER -