title: Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina.
abstract: OBJECTIVE
  The overall aim of this research work was to evaluate a series of dipeptide monoester prodrugs of an antiviral agent, ganciclovir (GCV), for oligopeptide transporter-targeted transscleral drug delivery to rabbit retina.
  
  
  METHODS
  The permeability and enzymatic hydrolysis of dipeptide monoester GCV prodrugs were evaluated using freshly excized rabbit retinal pigment epithelium (RPE)-choroidsclera (RCS) and sclera tissue preparations. Affinity and transport mechanism of these prodrugs and their translocation across RCS were investigated through competitive inhibition studies of [(3)H]glycylsarcosine with the prodrugs.
  
  
  RESULTS
  The transport of glycylsarcosine was found to be saturable (K(m) = 1.21 +/- 0.41 mM, V(max) = 15.89 +/- 1.54 pmoles/min/cm(2)), pH, temperature, and energy dependant. Dipeptides, angiotensin converting enzyme inhibitors, and a beta-lactum antibiotic strongly inhibited the transport of glycylsarcosine indicating the functional presence of oligopeptide transport (OPT) system on the RPE. Dipeptide prodrugs (valine-valine-GCV, glycine-valine-GCV, and tyrosine-valine-GCV), and valine-GCV demonstrate a high enzymatic stability and affinity toward the retinal OPT system. The transport of the prodrugs was significantly inhibited ( approximately 50%) in the presence of glycylsarcosine. The rank order of scleral permeability was Gly-Val-GCV approximately GCV>Val-GCV>Tyr-Val-GCV approximately Val-Val-GCV. The RCS permeability values of Val-GCV (3.29 +/- 0.09 x 10(6)cm/s), Val-Val-GCV (4.14 +/- 0.33 x 10(6)cm/s), Gly-Val-GCV (3.40 +/- 0.47 x 10(6)cm/s) and Tyr-Val-GCV (3.08 +/- 0.29 x 10(6)cm/s) were two-fold higher than that of GCV (1.61 +/- 0.06 x 10(6)cm/s).
  
  
  CONCLUSIONS
  The dipeptide monoester GCV prodrugs, owning to higher lipophilicity and OPT-mediated translocation across RPE, appear to be promising candidates in the treatment of ocular cytomegalovirus infections following an episcleral administration.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Viral
authors.initials: V
authors.lastname: Kansara
authors.forename: Yi
authors.initials: Y
authors.lastname: Hao
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002829:Choroid / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D015774:Ganciclovir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D012160:Retina / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism; D013329:Structure-Activity Relationship