title: Antiviral activity of phosphatidyl-dideoxycytidine in hepatitis B-infected cells and enhanced hepatic uptake in mice.
abstract: Dideoxycytidine (ddC) inhibits the replication of hepatitis B virus (HBV) but its clinical use is limited by peripheral neuropathy. We synthesized dioleoylphosphatidyl-ddC (DOP-ddC), a phospholipid prodrug of ddC which forms lipid bilayers and is readily incorporated into liposomes. The 90% effective dose (ED90) of DOP-ddC was 18 microM vs. 7 microM for ddC. However, in HBV-infected human hepatoma cells (2.2.15 cells), DOP-ddC was less toxic in vitro. When liposomal DOP-[5,6-3H]ddC was administered intraperitoneally to mice, drug levels in liver were 40 times greater than [5,6-3H]ddC when expressed as area under curve. Liposomal 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 ED90 six times longer with DOP-ddC than with ddC. DOP-ddC levels in sciatic nerve, the major site of toxicity, were not significantly different from levels observed with free ddC. The phospholipid prodrug approach is a general one which may readily be applied to other antiviral nucleosides for HBV.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla 92093-0676.
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: B E
authors.initials: BE
authors.lastname: Korba
authors.forename: C N
authors.initials: CN
authors.lastname: Sridhar
authors.forename: M F
authors.initials: MF
authors.lastname: Gardner
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers; D006509:Hepatitis B / Q000188:drug therapy* / Q000378:metabolism*; D008081:Liposomes; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D010715:Phosphatidylglycerols / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014018:Tissue Distribution; D014316:Tritium; D016047:Zalcitabine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D008081:Liposomes; D010715:Phosphatidylglycerols; D011355:Prodrugs; D014316:Tritium; C089810:1,2-dioleoyl-glycero-3-phospho-5'-(2',3')-dideoxycytidine; D016047:Zalcitabine