Abstract

henotype. To better characterize the activity of ODE-MPMPA eplicon rebound and compound uptake studies were performed. Methods: Huh-7.5.1 cells stably expressing the BM4-5 FEO eplicon (1b) were seeded in 96 well plates (2500 cells/well) and xposed to ODE-MPMPA at the EC50 (1.5 M) and EC90 (8 M). fter 48h compound was removed and replaced with complete edia. Luciferase expressionwasdeterminedand replication levels xpressed as a percentage of control wells. Cellular uptake studies ere performed in Huh7 cells with 8 M 14C-labeled MPMPA and DE-MPMPA. Results: Replications levels at 48hwere 52% and 8% at the EC50 nd EC90, respectively. At 96h after compound removal replication evels had declined further (23% and 2%). At one week replication emained suppressed (57% and 2%). After exposure to 8 M drug, ntracellular concentrations of radiolabeled MPMPA at 2, 4 and 4h were 43, 46 and 54pmol/106 cells compared with 330, 970 nd 3340pmol/106 cells for ODE-MPMPA. At 2, 4 and 24h, cellular evels of ODE-MPMPA were 8-, 21and 62-fold higher than those bserved with 8 M MPMPA. Conclusions: ODE-MPMPA displays potent and prolonged uppression of HCV replicon replication after a single expoure. Prolonged elevated intracellular concentrations of drug and etabolites lead to the delayed rebound on removal. High intraellular levels combined with the high fitness cost and/or low old-change of resistant mutants contribute to the high resistance arrier. Studies to determine the intracellular concentrations of the ctive metabolite (MPMPApp) are underway.

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