Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical 
development for the treatment and suppression of herpesviral diseases. The 
absolute bioavailability of acyclovir from valaciclovir and the metabolic 
disposition of valaciclovir were investigated with healthy volunteers in two 
separate studies. In a randomized, crossover study, 12 fasting healthy 
volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous 
infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir 
was 54.2%, a value three to five times that obtained previously with oral 
acyclovir. A similar estimate of 51.3% was made from urinary recovery of 
acyclovir. In the second study, four fasting volunteers received a single oral 
dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was 
accounted for by acyclovir, with very low plasma valaciclovir concentrations 
(mean maximum concentration of drug in plasma = 0.19 microM), which were 
undetectable after 3 h postdose. By 168 h, more than 90% of the administered 
radioactive dose was recovered, with approximately 45% in urine and 475 in 
feces. More than 99% of the radioactivity recovered in urine corresponded to 
acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 
8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for 
less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in 
fecal samples. These studies show that after oral administration to humans, 
valaciclovir is rapidly and virtually completely converted to acyclovir to 
provide a high level of acyclovir bioavailability in comparison with that 
following oral administration of acyclovir. The plasma acyclovir exposure 
obtained following oral administration of valaciclovir is similar to that 
achieved with doses of intravenous acyclovir, which are effective in the 
treatment and suppression of the less susceptible herpesviral diseases.