Intracellular metabolism of beta-L-ddAMP-bis(tbutylSATE), a potent inhibitor of hepatitis B virus replication.
beta-L-ddAMP-bis(tbutylSATE) is a potent inhibitor of HBV replication with an EC50 = 0.1 microM. Following a 0- to 72-hrs exposure of human hepatocytes to a 10 microM [2',3'-3H] beta-L-ddAMP-bis(tbutylSATE), the pharmacologically active beta-L-ddATP was the predominant metabolite attaining a concentration of 268.53 +/- 107.97 pmoles/10(6) cells at 2 hrs. In Hep-G2 cell, beta-L-ddATP accounted for 146.8 +/- 29.8 pmoles/10(6) cells at 2 hrs with an half life of approximately 5.4 hrs. This study reveals that extensive intracellular concentrations of beta-L-ddATP after incubation of cells to the parent drug is accounting for its potent antiviral activity.
Faraj
A
A
Department of Pharmacology, University of Alabama at Birmingham, USA.
Placidi
L
L
Perigaud
C
C
Cretton-Scott
E
E
Gosselin
G
G
Martin
L T
LT
Pierra
C
C
Schinazi
R F
RF
Imbach
J L
JL
Sommadossi
J P
JP
D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D003838:Deoxyadenine Nucleotides / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D003838:Deoxyadenine Nucleotides; C120722:ddAMP-bis(butylSATE)