Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir

Abstract

The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate β-ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37°C. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37°C. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate β-ester. The stability of all three esters decreased with increasing pH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p < 1%). L-Aspartate β-ester was absorbed to the extent of ∼8% over 90 min of perfusion at an initial drug concentration of 100 μM. Nasal absorption of L-aspartate β-ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate β-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:617–624, 2001