Novel Antiretroviral Chemotherapeutic Agents
Session Time: 4:30-6:30 pm
Background: Tenofovir is an acyclic nucleotide analog which has potent in vitro and in vivo activity against HIV. Tenofovir disoproxil (TDF), an oral prodrug of tenofovir, is approved for the treatment of HIV. After oral administration of TDF, only tenofovir is observed in plasma. Since tenofovir has low cellular permeability we sought to synthesize a novel prodrug of tenofovir which is orally bioavailable, stable in plasma and selectively metabolized inside cells.
Methods: GS 7340 was tested in a variety of in vitro and in vivo analyses. For PK studies, dogs and rhesus monkeys were dosed orally. Plasma and PBMCs were collected over 24 hours, and analyzed for tenofovir and GS 7340 by RP-HPLC. Tissue distribution of 14C-labeled GS 7340 was examined in dogs. Anti-HIV activity was determined using the MT-2 lymphoid cell line, mitogen-stimulated primary lymphocytes, and primary macrophages. Anti-HBV activity was assessed using the HepG2 2.2.15 hepatoblastoma cell line.
Results: After incubation in whole blood, GS 7340 was
stable in plasma but selectively metabolized to tenofovir
and the mono- and diphosphate species inside PBMCs. The bioavailability of tenofovir
after oral administration of GS 7340 in dogs and rhesus monkeys was
approximately 20%. After a single oral dose of GS 7340 in dogs and monkeys, the
concentration of tenofovir in PBMCs
(AUC0-24) was increased by >38-fold as compared with TDF. Efficient accumulation in lymphoid tissues
was also observed at 24 hours. In vitro, the EC50 against
HIV was approximately 5 nM in all cell types
examined; 5- to 10-fold more potent than TDF and 500- to 1000-fold more potent
than tenofovir. EC50 against HBV was
approximately 10 nM.
©2002 9th Conference on Retroviruses and Opportunistic Infections|