Bioreversion and Oral Bioavailability of the l ‐Valine Dipeptide Ester Prodrug of Acyclovir, Val‐Valacyclovir, in Sprague‐Dawley Rats

The overall objective of this study was to compare bioavailability of acyclovir (ACV) in Sprague‐Dawley (SD) rats following oral administration of the ACV prodrugs valacyclovir and val‐valacyclovir (10 mg/kg body weight ACV equivalent). ACV, valacyclovir and val‐valacyclovir were estimated using a high pressure liquid chromatography system equipped with a fluorescence detector. Intact prodrugs, valacyclovir and val‐valacyclovir could not be detected in the plasma. Differences in Cmax (4.47 ± 1.68 µg/ml and 2.92 ± 0.90 µg/ml), Tmax (51.66 ± 27.14 and 27.14 and 25.83 ± 11.14 min) and AUC (366.02 ± 146.78 and 231.3 ± 90.88 min. µg/ml) achieved for ACV derived from valacyclovir and val‐valacyclovir, respectively, were not statistically significant. Val‐valacyclovir was rapidly hydrolyzed in rat enterocyte and whole intestinal homogenates (half‐lives of 6.5 and 15 min respectively) and plasma (half‐life of 8.4 min). Valacyclovir demonstrated comparatively longer half‐lives in plasma (half‐life 466.9 min) and whole intestinal homogenates (half‐life 271.7 min) but was rapidly hydrolyzed to ACV in the enterocyte homogenates (half‐life 24.2 min). Both valacyclovir and val‐valacyclovir were rapidly hydrolyzed in liver homogenates. The short half‐lives of val‐valacyclovir in the biological matrices suggest rapid presystematic bioreversion to valacyclovir. This study reports for the first time that oral val‐valacyclovir generates systematic ACV levels comparable to those achieved with oral valacyclovir.