IN-VIVO ANTIVIRAL ACTIVITY AND PHARMACOKINETICS OF -1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL]CYTOSINE IN WOODCHUCK HEPATITIS VIRUS-INFECTEDWOODCHUCKS

The (-) enantiomer of 5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y l] cytosine [(-)-FTC)], a substituted oxathiolane compound with anti-h epatitis B virus activity in vitro, was assessed for its efficacy in w oodchucks with naturally acquired woodchuck hepatitis virus (WHV) infe ction, Pharmacokinetics and in vitro anabolism were also determined, ( -)-FTC was anabolized to the 5'-triphosphate in a dose-related fashion , reaching a maximum concentration at about 24 h in cultured woodchuck hepatocytes. Following administration of a dose of 10 mg/kg of body w eight intraperitoneally (i.p.), the clearance of (-)-FTC from plasma w as monoexponential, the terminal half-life was 3.76 +/- 1.4 h, and the systemic clearance was 0.12 +/- 0.06 liters/h/kg. The antiviral effic acy of (-)-FTC in the woodchuck model was assessed by quantitation of serum WHV DNA levels and by WHV particle-associated DNA polymerase act ivity at two dosages, 30 and 20 mg/kg given i.p. twice daily (b.i.d.), respectively, The level of WHV DNA in serum was reduced 20- to 150-fo ld (average, 56-fold) in the 30-mg/kg-b.i.d. treatment group and 6- to 49-fold (average, 27-fold) in the 20-mg/kg-b.i.d. treatment group, Vi ral DNA polymerase levels diminished accordingly, One week after treat ment was discontinued, WHV levels returned to pretreatment levels in b oth studies. These animals were biopsied before and following treatmen t with 30 mg of (-)-FTC per kg, Their livers were characterized by a m ild increase in cytoplasmic lipid levels, but this change was not asso ciated with altered liver enzyme levels, Serum chemistry and hematolog y results were within the normal ranges for all treated animals, We co nclude that (-)-FTC is a potent antihepadnaviral agent and that it has no detectable toxic effects in woodchucks when given for up to 25 day s, Further development of (-)-FTC as an anti-hepatitis B virus therapy for patients is warranted.