Interaction between Valproic Acid and Acyclovir after Intravenous and Oral Administration in a Rabbit Model

Abstract

This study was undertaken to investigate the effect of co-administration of valproic acid and acyclovir on the pharmacokinetic parameters of each other. Fifteen white New Zealand rabbits were divided into three groups: A, B and C. Group A received acyclovir only, group B received valproic acid only and group C received a combination of acyclovir and valproic acid. In a cross-over design, the intravenous route was studied first, followed by the oral route after a 2-week wash-out period. Blood samples were drawn over 10 hr and the pharmacokinetic parameters were derived from the concentrations. After intravenous administration, the area under the plasma concentration time curve and plasma concentrations of acyclovir in group C were higher than in group A, while the volume of distribution and plasma clearance of acyclovir in group C were only 12.8% and 10.36% of those of group A, respectively. A similar trend was observed after oral administration. However, the bioavailability (F) of acyclovir was 8.4% in group A versus 1.5% in group C. In addition, the concentrations and kinetic parameters of valproic acid between the two groups after oral and intravenous administration were not different. In conclusion, co-administration of single doses of acyclovir and valproic acid led to reduced oral bioavailability of acyclovir, but increased concentrations of acyclovir due to reduced volume of distribution and clearance. These observations call for a cautious approach to the concomitant use of the two drugs until human studies are done.