Disposition kinetics of a dipeptide ester prodrug of acyclovir and its metabolites following intravenous and oral administrations in rat

The objective of this work was to study the disposition kinetics of valine-valine-acyclovir (VVACV), a dipeptide ester prodrug of acyclovir following intravenous and oral administrations in rat. A validated LC-MS/MS analytical method was developed for the analysis VVACV, Valine-Acyclovir (VACV), and Acyclovir (ACV) using a linear Ion Trap Quadrupole. ACV was administered orally for comparison purpose. In the VVACV group, both blood and urine samples and in the ACV group only blood samples were collected. All the samples were analyzed using LC-MS/MS. The LLOQ for ACV, VACV, and VVACV were 10, 10, and 50 ng/ml, respectively. Relevant pharmacokinetic parameters were obtained by non-compartmental analyses of data with WinNonlin. Following i.v. administration of VVACV, AUC0-inf (min*μM) values for VVACV, VACV, and ACV were 55.06, 106, and 466.96, respectively. The AUC obtained after oral administration of ACV was 178.8. However, following oral administration of VVACV, AUC0-inf values for VACV and ACV were 89.28 and 810.77, respectively. Thus the exposure of ACV obtained following oral administration of VVACV was almost 6-fold higher than ACV. This preclinical pharmacokinetic data revealed that VVACV has certainly improved the oral bioavailability of ACV and is an effective prodrug for oral delivery of ACV.