Purchase this article with an account.
M. R. Gokulgandhi, R. Talluri, R. Gaudana, S. Hariharan, A. K. Mitra; To Investigate the Pharmacokinetics, Metabolism and Corneal Uptake of Novel Valine Based Stereoisomeric Dipeptide Prodrug of Acyclovir (ACV) in Rats After Oral Administration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5130.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Acyclovir (ACV) is an approved drug for the infection like genital herpes and herpes keratitis caused by herpes simplex virus (HSV). Previously, we have established the effect of incorporating a D-isomer in sterioisomeric dipeptide prodrug which has provided higher enzymatic stability due to modulation of the hydrolytic rate of both amidases and esterases. Therefore, the objective of this study was to investigate the pharmacokinetics, metabolism and corneal uptake of stable dipeptide prodrug of ACV, which can be targeted to peptide transporter present on blood aqueous barrier following oral administration in rats.
Pharmacokinetics of L-Valine-acyclovir (LACV) and L-Valine-D-Valine-Acyclovir (LDACV) were studied using Sprague-dawley male rats. Prodrugs were administered intravenously (i.v) as a bolus via jugular vein cannula and orally by gavage. Blood samples were collected and purified by protein precipitation method and were analyzed by LC-MS/MS. The pertinent pharmacokinetic parameters were obtained by using Winnonlin. Corneal uptake studies of LACV and LDACV were studied after oral administration.
Following i.v. administration of prodrugs, the area under the curve (AUC) represented in µM *min of generated ACV was in the order of LACV>LDACV indicating their rate of metabolism. The AUC values of total drug obtained after oral administration in the systemic circulation of LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 respectively. The Cmax (µM) and AUC of the intact prodrug obtained in the systemic circulation from LDACV were almost 4-5 times higher than that obtained with LACV. Corneal uptake after oral administration of LDACV was almost two fold higher than those obtained with LACV.
The valine based sterioisomeric prodrug LDACV has increased both the oral bioavailability and corneal uptake of ACV. Thus it seems to be the most promising candidate in treatment of genital herpes and herpes keratitis after oral administration.
This PDF is available to Subscribers Only