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Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis.
Drug Metab Dispos 2002; 30(6):670-5DM

Abstract

The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 microl/min. The drugs were administered (0.2 micromoles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t(1/2)beta) of GCV was found to be 426 +/- 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t(1/2k10)) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 +/- 37, 117 +/- 50, 122 +/- 13, 55 +/- 26, and 107 +/- 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3- to 4-fold through prodrug modification.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

12019194

Citation

Macha, Sreeraj, and Ashim K. Mitra. "Ocular Disposition of Ganciclovir and Its Monoester Prodrugs Following Intravitreal Administration Using Microdialysis." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 30, no. 6, 2002, pp. 670-5.
Macha S, Mitra AK. Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis. Drug Metab Dispos. 2002;30(6):670-5.
Macha, S., & Mitra, A. K. (2002). Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 30(6), pp. 670-5.
Macha S, Mitra AK. Ocular Disposition of Ganciclovir and Its Monoester Prodrugs Following Intravitreal Administration Using Microdialysis. Drug Metab Dispos. 2002;30(6):670-5. PubMed PMID: 12019194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis. AU - Macha,Sreeraj, AU - Mitra,Ashim K, PY - 2002/5/23/pubmed PY - 2002/10/11/medline PY - 2002/5/23/entrez SP - 670 EP - 5 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 30 IS - 6 N2 - The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 microl/min. The drugs were administered (0.2 micromoles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t(1/2)beta) of GCV was found to be 426 +/- 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t(1/2k10)) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 +/- 37, 117 +/- 50, 122 +/- 13, 55 +/- 26, and 107 +/- 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3- to 4-fold through prodrug modification. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/12019194/Ocular_disposition_of_ganciclovir_and_its_monoester_prodrugs_following_intravitreal_administration_using_microdialysis_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12019194 DB - PRIME DP - Unbound Medicine ER -