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 (λ z ). SACV and VACV exhibited approximately five fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C max(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. C last(T) (concentration at the last time point) of SACV was observed to be 0.18 ± 0.06 µM in plasma which is 2 times better than VACV and 3 times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C max ) and eliminated at varying rates (λ z ) 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.

Enhanced intracellular accumulation of a non-nucleoside anti-cancer agent via increased uptake of its valine ester prodrug through amino acid transporters

“…In particular, amino acid− mostly valine− ester prodrugs have gained much interest, because they enhance accumulation by influx transporters such as ATB 0,+ and PEPT1 (Balimane et al 1998;Ganapathy et al 1998;Guo et al 1999;Han et al 1998a;Han et al 1998b;Hatanaka et al 2004). However, the amino acid ester prodrug approach has been limited to nucleoside analogues (Li et al 2008), such as zidovudine (Han et al 1998a), levovirin (Li et al 2006), gemcitabine , floxuridine (Landowski et al 2005a;Landowski et al 2005b;Tsume et al 2008a;Tsume et al 2008b;Vig et al 2003), ara-C (Sun et al 2008), acyclovir (Anand et al 2004;Balimane et al 1998;de Miranda and Blum 1983;Ganapathy et al 1998;Guo et al 1999;Han et al 1998a;Han et al 1998b;Hatanaka et al 2004;Katragadda et al 2008;Majumdar et al 2009;Sawada et al 1999;Soul-Lawton et al 1995), and ganciclovir (Jung and Dorr 1999;Pescovitz et al 2000;Sugawara et al 2000;Umapathy et al 2004). Thus, it would be valuable to further investigate whether this promising amino acid ester prodrug strategy can be extended to non-nucleoside anti-cancer agents as well.…”

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

“…The all amino acid ester prodrugs examined showed affinity toward various amino acid transporters in addition to PEPT1, and the oral bioavailability of ACV was increased by approximately 5-fold with Ser-ACV and valacyclovir in rats. 50 The impact of PepT1 on the intestinal absorption of valacyclovir was confirmed by using PepT1 knockout (KO) mice, in which Cmax and area under the concentration-time curve (AUC) of ACV after oral administration of valacyclovir were 4-to 6-fold and 2-to 3-fold lower in KO mice, respectively, as compared with those in wildtype mice. 51,52 The usefulness of dipeptide ester prodrugs of ACV was also examined using Val-Val, Gly-Val, Gly-Gly, Gly-Tyr, Val-Try, and Tyr-Val ester moieties.…”

Transporter–metabolism interplay in the eye

“…An example of effl ux pump circumvention using the prodrug approach includes peptide prodrugs of acyclovir. Katragadda et al [74][75][76] studied the circumvention of P-gp-mediated effl ux by prodrug derivatization using isolated rabbit cornea. Peptide prodrugs of quinidine and acyclovir are reported to have a reduced affi nity toward P-gp and are suggested as a viable approach to overcome P-gp-mediated effl ux.…”