title: Cellular pharmacology of D-d4FC, a nucleoside analogue active against drug-resistant HIV.
abstract: The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 microM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.
authors.affiliation: DuPont Pharmaceuticals Co.(Bristol-Myers Squibb Pharmaceuticals Co.), Wilmington, Del., USA. serickson-viitanen@pharmasset.com
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Guoen
authors.initials: G
authors.lastname: Shi
authors.forename: Steven
authors.initials: S
authors.lastname: Unger
authors.forename: Robert W
authors.initials: RW
authors.lastname: King
authors.forename: Barbara
authors.initials: B
authors.lastname: Fish
authors.forename: Ronald
authors.initials: R
authors.lastname: Klabe
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Karen
authors.initials: K
authors.lastname: Gallagher
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016047:Zalcitabine / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009705:Nucleosides; D010835:Phytohemagglutinins; D018894:Reverse Transcriptase Inhibitors; D003570:Cytidine Triphosphate; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; C099405:dexelvucitabine