Reddy K Raja, Colby Timothy J, Fujitaki James M, van Poelje Paul D, Erion Mark D
Department of Chemistry, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, Building 300, San Diego, CA 92121, USA.
Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):375-81. doi: 10.1081/ncn-200059781.
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.
一类名为HepDirect前药的新型磷酸盐和膦酸盐前药已被开发出来，用于将药物输送到肝脏，同时减少药物在肝外组织中的暴露。该技术将肝脏选择性裂解和激酶旁路与高血浆和组织稳定性相结合，以提高肝脏中的药物水平。拉米夫定（LMV）是一种核苷类似物，是目前批准用于治疗乙型肝炎感染的药物，但由于磷酸化效率低下，其疗效一般且耐药性显著。在大鼠和人类肝细胞中，LMV不能充分磷酸化为相应的核苷三磷酸。相对于LMV，LMV单磷酸的一种HepDirect前药在大鼠肝细胞中产生的三磷酸水平高出34倍，在接受治疗的大鼠肝脏中三磷酸水平高出320倍。
Zotero 插件