Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′-triphosphate metabolite levels

The anti-human immunodeficiency virus (HIV) activity of abacavir (ABC; 1-(IS,4R)-4-12-amino-6-(cyclopropylamino)-9H-purin-9-y1]-2-cyclopentene- 1-methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro-ABC- MP) to virus-infected cell cultures. Metabolic studies with radiolabeled ABC and pro-ABC-MP in human T-lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC-MP) by pro-ABC-MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5'-triphosphate (CBV-TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC-MP and appearance of CBV-TP closely correlated with the extracellular pro-ABC-MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 muM. The highest amounts of CBV-TP were observed within 6-24 h after drug administration. The improved delivery of ABC-MP and metabolic conversion to CBV-TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.