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Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design.
J Ocul Pharmacol Ther 2002; 18(6):535-48JO

Abstract

Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity for mono-ester prodrugs having more than three carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 +/- 0.19 x 10(-6) cm sec(-1)) to its valerate ester prodrug (23.70 +/- 1.36 x 10(-6) cm sec(-1)). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy.

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 available

Pub Type(s)

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

Language

eng

PubMed ID

12537680

Citation

Tirucherai, Giridhar S., et al. "Corneal Permeation of Ganciclovir: Mechanism of Ganciclovir Permeation Enhancement By Acyl Ester Prodrug Design." Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, vol. 18, no. 6, 2002, pp. 535-48.
Tirucherai GS, Dias C, Mitra AK. Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design. J Ocul Pharmacol Ther. 2002;18(6):535-48.
Tirucherai, G. S., Dias, C., & Mitra, A. K. (2002). Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design. Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, 18(6), pp. 535-48.
Tirucherai GS, Dias C, Mitra AK. Corneal Permeation of Ganciclovir: Mechanism of Ganciclovir Permeation Enhancement By Acyl Ester Prodrug Design. J Ocul Pharmacol Ther. 2002;18(6):535-48. PubMed PMID: 12537680.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design. AU - Tirucherai,Giridhar S, AU - Dias,Clapton, AU - Mitra,Ashim K, PY - 2003/1/23/pubmed PY - 2003/4/24/medline PY - 2003/1/23/entrez SP - 535 EP - 48 JF - Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics JO - J Ocul Pharmacol Ther VL - 18 IS - 6 N2 - Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity for mono-ester prodrugs having more than three carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 +/- 0.19 x 10(-6) cm sec(-1)) to its valerate ester prodrug (23.70 +/- 1.36 x 10(-6) cm sec(-1)). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy. SN - 1080-7683 UR - https://www.unboundmedicine.com/medline/citation/12537680/Corneal_permeation_of_ganciclovir:_mechanism_of_ganciclovir_permeation_enhancement_by_acyl_ester_prodrug_design_ L2 - https://www.liebertpub.com/doi/full/10.1089/108076802321021081?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -