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(-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), and
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 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.