Effect of chitosan glutamate, carbomer 974P, and EDTA on the in vitro Caco-2 permeability and oral pharmacokinetic profile of acyclovir in rats.
BACKGROUND
Chitosan glutamate and polyacrylic acid (e.g., carbomer 974P) are known to modulate the tight junctions in the intestinal wall and increase permeability and blood exposure of drugs absorbed orally by the paracellular route.


OBJECTIVE
To assess the impact of chitosan glutamate and carbomer 974P on the absorption of paracellularly absorbed model drug, acyclovir, in vitro and in rat in vivo.


METHODS
The influence of chitosan glutamate and carbomer 974P (alone and in combination with EDTA-Na2) on the in vitro Caco-2 permeability and oral pharmacokinetic profile in the rat of acyclovir was investigated.


RESULTS
In the presence of chitosan glutamate, the apparent permeability of acyclovir across Caco2 monolayer increased 4.1 times relative to control. This increase was accompanied by a significant ( approximately 60%) decrease in transepithelial electrical resistance values indicating opening of the tight junctions in the cell monolayer. In rat, chitosan glutamate doubled oral bioavailability of acyclovir and tripled the amount of acyclovir excreted unchanged into urine. In contrast, the effect of carbomer 974P was not statistically significant at 5% level.


CONCLUSIONS
In conclusion, chitosan glutamate (1-3%) and chitosan glutamate (1%)/EDTA-Na2 (0.01%) are effective excipients to increase permeability of acyclovir across Caco-2 cell monolayers and the oral absorption in the rat in vivo.
Merzlikine
Alexei
A
Department of Pharmaceutical Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT, USA.
Rotter
Charles
C
Rago
Brian
B
Poe
Julie
J
Christoffersen
Curt
C
Thomas
V Hayden
VH
Troutman
Matthew
M
El-Kattan
Ayman
A
D000179:Acrylates / Q000737:chemistry*; D000212:Acyclovir / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004492:Edetic Acid / Q000737:chemistry*; D017097:Electric Impedance; D005079:Excipients; D005971:Glutamates / Q000737:chemistry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley
D000179:Acrylates; D000998:Antiviral Agents; D005079:Excipients; D005971:Glutamates; C117167:carbopol 974P NF; D048271:Chitosan; D004492:Edetic Acid; D000212:Acyclovir