Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Abstract

In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, l-alanine-ACV (AACV), l-serine-ACV (SACV), l-isoleucine-ACV (IACV), γ-glutamate-ACV (EACV) and l-valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied. In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (λz). SACV and VACV exhibited approximately five-fold increase in area under the curve (AUC) values relative to ACV (p < 0.05). Cmax(T) (maximum concentration) of SACV was observed to be 39 ± 22 μM in plasma which is 2 times better than VACV and 15 times better than ACV. Clast(T) (concentration at the last time point) of SACV was observed to be 0.18 ± 0.06 μM in plasma which is two times better than VACV and three times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (Cmax) and eliminated at varying rates (λz) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections. © 2008 Elsevier B.V. All rights reserved.