Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 1. Acyclovir

Abstract

The acyclic nucleoside analogue, acyclovir, is an antiviral drug with activity against the herpes group of DNA viruses. Clinically, it is used as a selective therapeutic agent for the treatment of herpes simplex and varicella-zoster virus infections. Studies on the disposition of acyclovir, during the course of its preclinical and clinical development, indicated significant species differences in the absorption, metabolism and elimination of the drug. Gastrointestinal absorption was adequate in dogs and in mice; but in rats and primates it was limited to less than 20% of the administered dose. Whereas in some species (mice, rats, and dogs), acyclovir was virtually unmetabolized, significant biotransformation was apparent in guinea pigs, rabbits, and some primates. Acyclovir tissue distribution was extensive and indicated few differences across species. This review summarizes diverse studies on acyclovir absorption, metabolism, and disposition in different species, including humans, and indicates the relevance and importance of such studies in drug development.