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

Abstract

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) is a nucleoside analog that was rationally designed as a more chemically and enzymatically stable anti-AIDS drug than its parent compound 2', 3'-dideoxyadenosine or didanosine. Plasma and cerebrospinal fluid (CSF) pharmacokinetics of this compound 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 administered as an i.v. push. F-ddA exhibited a mean residence time of 0.17 h in plasma and its plasma concentration time profile appeared to be biexponential. The majority of plasma exposure was from F-ddI, with a mean parent drug area 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 one-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 greater than it was after administration of F-ddA; however, the CSF AUC to plasma AUC ratio was a factor of 4 lower (0.017). Thus, F-ddA central nervous system penetration is at least comparable to that of didanosine, indicating that this experimental drug has potential as an addition to currently approved AIDS therapies.

• Authors: J S Roth, C M McCully, F M Balis, D G Poplack, J A Kelley
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 27 Issue 10 Pg. 1128-32 (Oct 1999) ISSN: 0090-9556 [Print] United States
• PMID: 10497138 (Publication Type: Journal Article)

Chemical References

• Anti-HIV Agents
• lodenosine
• Dideoxyadenosine

Topics

• Animals
• Anti-HIV Agents (pharmacokinetics)
• Dideoxyadenosine (analogs & derivatives, blood, cerebrospinal fluid, pharmacokinetics)
• Macaca mulatta
• Male