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Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina.
J Ocul Pharmacol Ther 2007; 23(4):321-34JO

Abstract

PURPOSE

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+Show Affiliations

Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17803430

Citation

Kansara, Viral, et al. "Dipeptide Monoester Ganciclovir Prodrugs for Transscleral Drug Delivery: Targeting the Oligopeptide Transporter On Rabbit Retina." Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, vol. 23, no. 4, 2007, pp. 321-34.
Kansara V, Hao Y, Mitra AK. Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina. J Ocul Pharmacol Ther. 2007;23(4):321-34.
Kansara, V., Hao, Y., & Mitra, A. K. (2007). Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina. Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, 23(4), pp. 321-34.
Kansara V, Hao Y, Mitra AK. Dipeptide Monoester Ganciclovir Prodrugs for Transscleral Drug Delivery: Targeting the Oligopeptide Transporter On Rabbit Retina. J Ocul Pharmacol Ther. 2007;23(4):321-34. PubMed PMID: 17803430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina. AU - Kansara,Viral, AU - Hao,Yi, AU - Mitra,Ashim K, PY - 2007/9/7/pubmed PY - 2007/11/9/medline PY - 2007/9/7/entrez SP - 321 EP - 34 JF - Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics JO - J Ocul Pharmacol Ther VL - 23 IS - 4 N2 - PURPOSE: 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. SN - 1080-7683 UR - https://www.unboundmedicine.com/medline/citation/17803430/Dipeptide_monoester_ganciclovir_prodrugs_for_transscleral_drug_delivery:_targeting_the_oligopeptide_transporter_on_rabbit_retina_ L2 - https://www.liebertpub.com/doi/full/10.1089/jop.2006.0150?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -