Effect of Mono‐ and Di‐acylation on the Ocular Disposition of Ganciclovir: Physicochemical Properties, Ocular Bioreversion, and Antiviral Activity of Short Chain Ester Prodrugs

Dias, Clapton; Anand, Banmeet; Mitra, Ashim K.

doi:10.1002/jps.10072

Cited by 47 publications

(41 citation statements)

References 13 publications

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“…The ocular homogenate studies showed that the hydrolysis rate of the prodrugs increased with the ester chain length (Dias et al, 2002). The prodrugs generated GCV primarily due to the esterase activity, acetylcholine and butyrylcholine esterases, in all the ocular tissues (i.e., retina-choroid, iris-ciliary, lens, vitreous and aqueous humors) (Lee et al, 1985).…”

Section: Ocular Disposition Of Gcv and Its Monoester Prodrugsmentioning

confidence: 99%

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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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 l/min. The drugs were administered (0.2 moles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t 1/2 ␤) 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.

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Section: Ocular Disposition Of Gcv and Its Monoester Prodrugsmentioning

confidence: 99%

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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“…Lipophilic acyl ester derivatization is a strategy to improve ocular bioavailability and permeation across cell membrane barriers. Earlier we reported synthesis, ocular disposition and antiviral efficacy of mono and di-acyl esters of small carbon chain conjugated GCV derivatives [21]. GCV lipid prodrugs not only improved ocular bioavailability of GCV, but the ester bond hydrolysed slowly producing sustained GCV levels.…”

Section: Introductionmentioning

confidence: 91%

Untitled

2014

AOVS

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H) and carbon ( 13 C) nuclear magnetic resonance and mass spectroscopy. Also, melting point and lipophilicity for the prodrugs and GCV were determined. MTS assay was used to assess in vitrotoxicity of GCV and its long chain lipid prodrugs on human retinal pigment epithelial cell line (ARPE-19) cells. Results indicated that long chain lipid GCV prodrugs are nontoxic, safe and well-tolerated by ARPE-19 cells. These results suggest that novel long chain lipid GCV prodrugs may be further evaluated for ocular delivery and treatment of HCMV retinitis.

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“…Octanol/water partition coefficient P o/w, of sinomenine was determined by shake flask method that was based on thorough mixing of the two phases to reach the equilibrium 9,10 . Stock solutions of sinomenine were made in aqueous solution with pH of 2, 3, 4, 5, 6, 7, 8, 9, 10 adjusted with hydrochloride solution or sodium hydroxide solution, and then presaturated with the analytic grade n-octanol.…”

Section: Partition Coefficient Determinationmentioning

confidence: 99%

Penetration effect of Ostrich Oil as a Promising Vehicle on Transdermal Delivery of Sinomenine

et al. 2013

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Effect of Mono‐ and Di‐acylation on the Ocular Disposition of Ganciclovir: Physicochemical Properties, Ocular Bioreversion, and Antiviral Activity of Short Chain Ester Prodrugs

Cited by 47 publications

References 13 publications

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Untitled

Penetration effect of Ostrich Oil as a Promising Vehicle on Transdermal Delivery of Sinomenine

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