Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system

Objective: Improved therapy for AIDS dementia and related encephalopathies may be achieved through enhanced delivery of effective antiretroviral agents to the central nervous system (CNS). Design: A novel chemical delivery system (CDS) was used, which utilized redox trapping of drugs in the brain. This study was aimed at defining the pharmacokinetics of a zidovudine (ZDV)-CDS as well as establishing its in vitro antiviral efficacy against HIV in both lymphocytes and in a neural cell line. Results: ZDV-CDS administered parenterally to rats produced significantly higher brain levels of ZDV [area under the curve (AUG), 425 μg x min/g] than equimolar ZDV (AUG, 13.5 μg x min/g). Native ZDV uptake was minimal after 1 h when analyzed in CEM lymphocytes and in SKNMC neuroblastoma cell line. By contrast, marked uptake of ZDV-CDS was followed by biochemical conversion of ZDV-CDS to its main metabolites (ZDV-CDS quaternary salt, ZDV-Q+, and native ZDV). These improved uptake profiles were associated with greater in vitro virucidal effect. ZDV-CDS at 0.5 μM was 80% more effective than ZDV in suppressing p24 production in a lymphocyte culture infected with 6000 median tissue culture infective doses (TCID₅₀) of the HIV N1T strain and 50% more effective at 0.05 μM. Furthermore, syncytia formation was completely suppressed at a ZDV-CDS dose of 0.5 μM (600TCID₅₀) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 μM) is not active in reducing viral replication in an SKNMC neural cell line, the ZDV-CDS complex significantly suppressed p24 synthesis. Conclusion: The ZDV-CDS complex is capable of delivering higher ZDV doses to lymphocytes and neural cells, with improved antiretroviral activity.