Single dose and multiple dose pharmacokinetics of 2 '-fluoro-2 ',3'-dideoxyadenosine and 2 '-fluoro-2 ',3 '-dideoxyinosine, anti-HIV agents, in rats

A single and multiple dose pharmacokinetic (PK) study was conducted in rats following oral administration of 2'-fluoro-2',3'-dideoxyadenosine (FddA) a nd 2'-fluoro-2',3'-dideoxyinosine (FddI) at three dose levels. Six rats/gen der were assigned to one of the three FddA or FddI dose levels. 40, 250, an d 1000 mg/kg/day. Three rats/gender were assigned to the PK study on day 1, while the remaining 3 rats/gender were assigned to the PK study on day 14. The rats received the appropriate doses of either FddA or FddI orally by g avage once a day for 14 days. Serial blood samples up to 24 h and cumulativ e urine samples (0-24 h) were collected on both days 1 and 14. Plasma and u rine samples were analyzed for the concentrations of intact FddA and/or Fdd I using a validated assay. The data were subjected to non-compartmental PK analyses. Over the dose range of 40-1000 mg/kg, both FddA and FddI exhibited dose dep endent pharmacokinetics in rats. Following FddA administration, there was a rapid and extensive in vivo conversion of FddA to FddI; FddI was the major circulating moiety as reflected by C-max and AUC values (generally 2-3-fol d greater than those of FddA at each dose level) as well as the amount excr eted (%UR) in the urine. In contrast, following FddI administration, C-max, AUC, and %UR values were 2-5-fold lower as compared to the FddI generated from FddA administration at each dose level, which also suggested that FddI was not absorbed as extensively as FddA. Based on the findings of this stu dy, FddA is an excellent prodrug of FddI.