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Pharmaceutical Research

, Volume 11, Issue 2, pp 237–242 | Cite as

The Physicochemical Properties, Plasma Enzymatic Hydrolysis, and Nasal Absorption of Acyclovir and Its 2′-Ester Prodrugs

  • Zezhi Shao
  • Gee-Bae Park
  • Ramesh Krishnamoorthy
  • Ashim K. Mitra
Article

Abstract

A series of 2′-(O-acyl) derivatives of 9-(2-hydoxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.

acyclovir aqueous solubility 2′-ester prodrugs lipophilicity nasal delivery plasma bioconversion 

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Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Zezhi Shao
    • 1
  • Gee-Bae Park
    • 1
  • Ramesh Krishnamoorthy
    • 1
  • Ashim K. Mitra
    • 1
  1. 1.Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal SciencesPurdue UniversityWest Lafayette

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