2 '-beta-fluoro-2 ',3 '-dideoxyadenosine, lodenosine, in rhesus monkeys: Plasma and cerebrospinal fluid pharmacokinetics and urinary disposition

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) is a nucleoside a nalog that was rationally designed as a more chemically and enzymatically s table anti-AIDS drug than its parent compound 2',3'-dideoxyadenosine or did anosine. Plasma and cerebrospinal fluid (CSF) pharmacokinetics of this comp ound and its major metabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), were studied in three rhesus monkeys after a single 20 mg/kg dose administ ered as an i.v. push. F-ddA exhibited a mean residence time of 0.17 h in pl asma and its plasma concentration time profile appeared to be biexponential . The majority of plasma exposure was from F-ddI, with a mean parent drug a rea under the curve (AUC) to metabolite AUC ratio of 0.16. CSF levels were low, with a mean CSF AUC to plasma AUC ratio of 0.068, with approximately o ne-quarter of this exposure in CSF due to unchanged drug. Urinary excretion accounted for half of the drug administered with the majority recovered as the metabolite, F-ddI. In a separate experiment, one monkey received a 20 mg/kg i.v. dose of F-ddI. The total dideoxynucleoside plasma exposure was g reater than it was after administration of F-ddA; however, the CSF AUC to p lasma AUC ratio was a factor of 4 lower (0.017). Thus, F-ddA central nervou s system penetration is at least comparable to that of didanosine, indicati ng that this experimental drug has potential as an addition to currently ap proved AIDS therapies.