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.
OBJECTIVE
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.


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.
Anand
Banmeet S
BS
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.
Katragadda
Suresh
S
Nashed
Yasser E
YE
Mitra
Ashim K
AK
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D004355:Drug Stability; D005240:Feasibility Studies; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018259:Herpesvirus 1, Human; D006868:Hydrolysis; D066298:In Vitro Techniques; D016849:Keratitis, Herpetic / Q000378:metabolism*; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics*; D011817:Rabbits; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D026905:Amino Acid Transport Systems; D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; D000998:Antiviral Agents; D011355:Prodrugs; C495023:gamma-glutamylacyclovir; C495024:tyrosylacyclovir; D018698:Glutamic Acid; D014443:Tyrosine; D000212:Acyclovir