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S Dey, Y Nashed, B Jain, AK Mitra; -Glu-Acv ( Glutamate Ester of Acyclovir): A Soluble Amino Acid Ester of Acyclovir for HSV-1 Keratitis: Synthesis, Stability and Corneal Permeability . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3255.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Herpes Simplex Virus (HSV) is the single most frequent cause of corneal opacities in developed countries. The objective of this research is to develop novel prodrug strategy for one acycloguanosine based antiviral agent, acyclovir (ACV) and to improve its corneal permeability. Methods: The model compound used to improve corneal permeability was γ-Glu-ACV. ACV was dissolved in DMF and treated with a solution N-Boc and O-tBu protected glutamic acid anhydride at 25 ºC for 24 hrs. The resulting compound was deprotected with TFA and washed with ethyl ether. Stability studies were done in USP specified buffers in the pH range of 1.2-9.0 at 25 ºC. These studies were carried out for at least 72 hrs. For corneal transport experiments, freshly excised albino rabbit corneas were used. γ-Glu-ACV was used in the concentration range of 0.25-1.0 mM. HPLC was used to analyze the samples. Mobile phase consisted of 25 mM KH2PO4 and acetonitrile (98:2) at pH 2.5 and detected at 257 nm. Results: γ-Glu-ACV was found to be least stable at pH 9.0 and its maximum stability was at pH 1.2. It is found to undergo base catalyzed hydrolysis. The degradation half-lives (t1/2) ranged from 62 min at pH 9.0 to 180 hrs at pH 2.6. No detectable degradation was seen at pH 1.2 in 7 days. The permeabilities of γ-Glu-ACV and ACV were found to be 4.02 x 10-6 cm/sec and 1.33 x 10-6 cm/sec respectively. The transport of 14C Glycine was inhibited by γ-Glu-ACV, the permeabilities being 9.4 x 10-6 ( 1.5 x 10-6) cm/s and 4.1 x 10-6 (1.5 x 10-6) cm/s in the absence and presence of 1 mM γ-Glu-ACV. Conclusion: γ-Glu-ACV was found to have better aqueous solubility than ACV (25 mg/ml compared to 1.3 mg/ml). Hydrolysis was found to occur primarily by specific base catalysis. Preliminary results indicate that γ-Glu-ACV is a substrate for Glycine transport system. Corneal permeability of γ-Glu-ACV was increased 3 times as compared to ACV. The prodrug strategy was successful in improving the corneal permeability of ACV.
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