[Liver targeting of hepatitis-B antiviral lamivudine using the HepDirect prodrug technology]
>> Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):375-81.
Liver targeting of hepatitis-B antiviral lamivudine using the HepDirect prodrug technology.
Reddy KR, Colby TJ, Fujitaki JM, van Poelje PD, Erion MD.
Department of Chemistry, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, Building 300, San Diego, CA 92121, USA.
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.<<
LMV is a low hurdle, but Pradefovir beats up Hepsera, too, (as I'm sure you know, but documenting it here). See my recent JPM notes concerning the comparison to Hepsera, the other LMV prodrug.
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Cheers, Tuck |
