Received for publication April 19, 2004.
Revised June 11, 2004.
Accepted for publication June 14, 2004.

Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir Following Oral Administration: Intestinal absorption and Liver Metabolism

Abstract

The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV) is an effective anti-herpetic drug. Systemic availability of ACV in humans is 3-5 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 towards the intestinal oligopeptide transporter hPEPT1 and therefore appear 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 following oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The area under plasma-concentration time curves (AUC) expressed as min µg ml^-1 for total concentration of VACV (208.4 ± 41.2) and the dipeptide prodrugs, Gly-Val-ACV (GVACV) (416.1 ± 140.9); Val-Val-ACV (VVACV) (147.7 ± 89.3); Val-Tyr-ACV (VYACV) (180.7 ± 81.2) were significantly higher than that of ACV (21.2 ± 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 as compared to intestinal absorption of GVACV and VVACV. The dipeptide prodrugs of ACV exhibited higher systemic availability of regenerated ACV upon oral administration and thus appear to be promising drug candidates in treatment of oral and genital herpes infections.

Key words: Antivirals, Herpes, Metabolsim, Peptide Transporter, Pharmacokinetics, Prodrugs