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Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits.
J Ocul Pharmacol Ther 2006; 22(6):465-76JO

Abstract

AIM

The overall aim of this study was to evaluate the corneal absorption of dipeptide monoester prodrugs of ganciclovir (GCV) and compare these results with L-valine-GCV and GCV. Another aim was to evaluate the pharmacokinetics of these prodrugs in aqueous humor.

METHODS

A well was placed on the cornea of anesthetized New Zealand albino rabbits with linear probes implanted in the aqueous humor. Two hundred microlitres (200 microL) of a 0.43% w/v (saturation concentration) solution of GCV and equimolar concentrations of its prodrugs, VGCV, glycine-valine-GCV (GVGCV), valine-valine-GCV (VVGCV), and tyrosine-valine- GCV (YVGCV), were placed in the corneal well and were allowed to diffuse for a period of 2 h. Subsequently, the drug solution was aspirated and the well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by high-performance liquid chromatography to determine the aqueous humor concentrations.

RESULTS

Area under the concentration time profile (AUC)infinity and maximum concentration (Cmax) of YVGCV were found to be higher than other prodrugs. AUC of total GCV obtained from YVGCV administration was found to be twelvefold more than AUC of GCV and 6.2-fold more than AUC obtained with total GCV from VGCV administration. VVGCV also exhibited 3.2 times higher AUC relative to VGCV. Also, AUC and Cmax of regenerated GCV from YVGCV was 8.6 and 4.9 times more than GCV, respectively. VVGCV did not produce higher concentrations of GCV. Elimination half-life of regenerated GCV from YVGCV administration was observed to be 157 min.

CONCLUSIONS

YVGCV and VVGCV exhibited superior corneal absorption and bioavailability, in comparison with GVGCV, VGCV, and GCV. Such facilitated absorption of prodrugs may be a result of a combination of transcellular passive diffusion and peptide transporter (PEPT1)-mediated transport across the corneal epithelium.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110-2499, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17238815

Citation

Gunda, Sriram, et al. "Corneal Absorption and Anterior Chamber Pharmacokinetics of Dipeptide Monoester Prodrugs of Ganciclovir (GCV): in Vivo Comparative Evaluation of These Prodrugs With Val-GCV and GCV in Rabbits." Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, vol. 22, no. 6, 2006, pp. 465-76.
Gunda S, Hariharan S, Mitra AK. Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits. J Ocul Pharmacol Ther. 2006;22(6):465-76.
Gunda, S., Hariharan, S., & Mitra, A. K. (2006). Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits. Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, 22(6), pp. 465-76.
Gunda S, Hariharan S, Mitra AK. Corneal Absorption and Anterior Chamber Pharmacokinetics of Dipeptide Monoester Prodrugs of Ganciclovir (GCV): in Vivo Comparative Evaluation of These Prodrugs With Val-GCV and GCV in Rabbits. J Ocul Pharmacol Ther. 2006;22(6):465-76. PubMed PMID: 17238815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits. AU - Gunda,Sriram, AU - Hariharan,Sudharshan, AU - Mitra,Ashim K, PY - 2007/1/24/pubmed PY - 2007/2/24/medline PY - 2007/1/24/entrez SP - 465 EP - 76 JF - Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics JO - J Ocul Pharmacol Ther VL - 22 IS - 6 N2 - AIM: The overall aim of this study was to evaluate the corneal absorption of dipeptide monoester prodrugs of ganciclovir (GCV) and compare these results with L-valine-GCV and GCV. Another aim was to evaluate the pharmacokinetics of these prodrugs in aqueous humor. METHODS: A well was placed on the cornea of anesthetized New Zealand albino rabbits with linear probes implanted in the aqueous humor. Two hundred microlitres (200 microL) of a 0.43% w/v (saturation concentration) solution of GCV and equimolar concentrations of its prodrugs, VGCV, glycine-valine-GCV (GVGCV), valine-valine-GCV (VVGCV), and tyrosine-valine- GCV (YVGCV), were placed in the corneal well and were allowed to diffuse for a period of 2 h. Subsequently, the drug solution was aspirated and the well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by high-performance liquid chromatography to determine the aqueous humor concentrations. RESULTS: Area under the concentration time profile (AUC)infinity and maximum concentration (Cmax) of YVGCV were found to be higher than other prodrugs. AUC of total GCV obtained from YVGCV administration was found to be twelvefold more than AUC of GCV and 6.2-fold more than AUC obtained with total GCV from VGCV administration. VVGCV also exhibited 3.2 times higher AUC relative to VGCV. Also, AUC and Cmax of regenerated GCV from YVGCV was 8.6 and 4.9 times more than GCV, respectively. VVGCV did not produce higher concentrations of GCV. Elimination half-life of regenerated GCV from YVGCV administration was observed to be 157 min. CONCLUSIONS: YVGCV and VVGCV exhibited superior corneal absorption and bioavailability, in comparison with GVGCV, VGCV, and GCV. Such facilitated absorption of prodrugs may be a result of a combination of transcellular passive diffusion and peptide transporter (PEPT1)-mediated transport across the corneal epithelium. SN - 1080-7683 UR - https://www.unboundmedicine.com/medline/citation/17238815/Corneal_absorption_and_anterior_chamber_pharmacokinetics_of_dipeptide_monoester_prodrugs_of_ganciclovir__GCV_:_in_vivo_comparative_evaluation_of_these_prodrugs_with_Val_GCV_and_GCV_in_rabbits_ L2 - https://www.liebertpub.com/doi/full/10.1089/jop.2006.22.465?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -