Valaciclovir

Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir.

Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form.

The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for thymidine kinase (TK).

In summary, the antiviral effects of valacyclovir are achieved in 3 ways:

1) competitive inhibition of viral DNA polymerase

2) incorporation and termination of the growing viral DNA chain

3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK).