Targeting of Acyclovir to the Brain via a Lipophilic and Water Soluble Prodrug
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Authors
Melson, Josh
Issue Date
1993
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
[9-(2-hydroxyethoxymethyl)guanine] or acyclovir (ACV) is a nucleoside
analog that has high antiviral activity for herpes simplex virus (HSV) (Laskin,
1984). While oral dosage forms have been successful in ceasing viral shedding
in genital infections, oral forms of ACV do not reach adequate levels to inhibit
viral replication in the CNS (Corey, 1985). This is due to 1) low bioavailability
of ACV to the plasma following oral administration and 2) restriction of
transport of the relatively polar ACV to the brain by the blood brain barrier
(BBB). We synthesized ester prodrugs of ACV to create a prodrug of ACV that
could cross the BBB by passive diffusion thereby increasing concentration of
ACV in the brain. Lipophilicity studies indicate that esters with chains of C5
and longer should be able to diffuse passively across the BBB. Ester prodrugs
must be reconverted back to the parent form to be active. Use of the inhibitor
PMSF showed significant inhibition on the degradation of the esters implying
that esterase activity is present, reconverting the prodrug back to the active
form. Esterase activity was found to be dependent upon the structure of the
ester substituent. Lipophilicity increases were accompanied with decreases in
aqueous solubility which is thought to restrict bioavailability of an oral dosage
(Krenitsky,1986). A scheme to enhance solubility by removal of an exocyclic
amino group was not found to produce increases in solubility adequate for an
oral form.
Description
v, 34 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.