ANTIVIRAL ACTIVITY OF PHOSPHATIDYL-DIDEOXYCYTIDINE IN HEPATITIS B-INFECTED CELLS AND ENHANCED HEPATIC-UPTAKE IN MICE

Dideoxycytidine (ddC) inhibits the replication of hepatitis B virus (H BV) but its clinical use is limited by peripheral neuropathy. We synth esized dioleoylphosphatidyl-ddC (DOP-ddC), a phospholipid prodrug of d dC which forms lipid bilayers and is readily incorporated into liposom es. The 90% effective dose (ED(90)) of DOP-ddC was 18 mu M vs. 7 mu M for ddC. However, in HBV-infected human hepatoma cells (2.2.15 cells), DOP-ddC was less toxic in vitro. When liposomal DOP-[5,6-H-3]ddC was administered intraperitoneally to mice, drug levels in liver were 40 t imes greater than [5,6-H-3]ddC when expressed as area under curve. Lip osomal DOP-ddC also provided higher levels of drug in lymph nodes and spleen, important accessory sites of HBV replication. Plasma levels of drug remained above the ED(90) six times longer with DOP-ddC than wit h ddC. DOP-ddC levels in sciatic nerve, the major site of toxicity, we re not significantly different from levels observed with free ddC. The phospholipid prodrug approach is a general one which may readily be a pplied to other antiviral nucleosides for HBV.