Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism

Abstract

The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV), is an effective antiherpetic drug. Systemic availability of ACV in humans is 3 to 5 times higher after oral administration of VACV. Enhanced bioavailability of VACV has been attributed to its carrier-mediated intestinal absorption via hPEPT1 peptide transporter followed by rapid and complete conversion to ACV. An earlier report suggested that the dipeptide ester prodrugs of ACV possess high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of oral herpes virus infections. In the present study, we have examined the bioavailability of a series of dipeptide prodrugs of ACV after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The area under plasma-concentration time curves expressed as minutes microgram milliliter Ϫ1 for total concentration of VACV (208.4 Ϯ 41.2), and the dipeptide prodrugs Gly-Val-ACV (GVACV) (416.1 Ϯ 140.9), Val-Val-ACV (VVACV) (147.7 Ϯ 89.3), and Val-Tyr-ACV (VYACV) (180.7 Ϯ 81.2) were significantly higher than that of ACV (21.2 Ϯ 5.2) upon intestinal absorption. Interestingly, the bioavailability of ACV after administration of GVACV was approximately 2-fold higher than VACV. There was significant metabolism by hepatic first pass effect of the dipeptide prodrugs as evident by the higher levels of ACV obtained after systemic absorption compared with intestinal absorption of GVACV and VVACV. The dipeptide prodrugs of ACV exhibited higher systemic availability of regenerated ACV upon oral administration and thus seem to be promising drug candidates in treatment of genital herpes infections.Peptide transporters PepT1 and PepT2 are perhaps the drug transporters that have captured the most recent attention in drug delivery. Small peptides such as di-and tripeptides are transported by PepT1 and PepT2 in intestinal and renal epithelial cells, respectively. Structure, function, mechanism, and substrate specificity of the peptide transporters have been extensively studied

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

“…Intestinal peptide transporter especially PEPT1, has been a key target protein for prodrug design. Several prodrugs have already been designed such that the modified compounds become substrates of peptide transporters leading to enhanced absorption of these compounds across various physiological barriers (Rousselle et al, 2000;Rouquayrol et al, 2002;Rice et al, 2003;Anand et al, 2004). When a substrate binds to a nutrient transporter it triggers a configurational change in the transport protein as a result of which it is translocated across the membrane and released into the cell cytoplasm.…”

Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir

“…12,13 Elucidation of that process will require in vitro metabolism studies or further in vivo models. 27 BRL423596 has very low cytotoxicity in vitro, which is fortunate given the high plasma BRL42359 concentrations that accumulated in the cats of the present study following famciclovir administration; however, it also has no efficacy against FHV-1 in vitro. 2 Results of the present study provided data that advanced the understanding of the PK of penciclovir in tears, which is critical if famciclovir is to be used to treat herpetic disease that involves the ocular surface, especially the avascular cornea.…”

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

“…Strategies have been used to design prodrugs of various poorly absorbed drugs targeted toward receptors/transporters to improve systemic bioavailability (Anand et al, 2004a;Anand et al, 2004b;Steffansen et al, 2004;Tolle-Sander et al, 2004). Valacyclovir (VACV) is such a prodrug that is derived from acyclovir (ACV) by esterifying 3-hydroxyl group of ACV with L-valine.…”