title: Liver targeting of hepatitis-B antiviral lamivudine using the HepDirect prodrug technology.
abstract: A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, has been developed to deliver drugs to the liver while simultaneously diminishing drug exposure to extra-hepatic tissues. The technology combines liver-selective cleavage and kinase by pass with high plasma and tissue stability to achieve increased drug levels in the liver. Lamivudine (LMV), a nucleoside analogue, is a currently approved treatment for hepatitis B infection, but shows modest efficacy and significant drug resistance due to inefficient phosphorylation. LMV is inadequately phosphorylated to the corresponding nucleoside triphosphate in rat and human hepatocytes. A HepDirect prodrug of LMV monophosphate generated 34-fold higher levels of the triphosphate in rat hepatocytes and 320-fold higher triphosphate levels in the liver of treated rats relative to LMV.
authors.affiliation: Department of Chemistry, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, Building 300, San Diego, CA 92121, USA.
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Colby
authors.forename: James M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002478:Cells, Cultured; D006509:Hepatitis B / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D019259:Lamivudine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000821:virology*; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D010710:Phosphates; D011355:Prodrugs; D019259:Lamivudine