title: 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.affiliation: Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. rothj@dc37a.nci.nih.gov
authors.forename: J S
authors.initials: JS
authors.lastname: Roth
authors.forename: C M
authors.initials: CM
authors.lastname: McCully
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: D G
authors.initials: DG
authors.lastname: Poplack
authors.forename: J A
authors.initials: JA
authors.lastname: Kelley
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008297:Male
chemical_list: D019380:Anti-HIV Agents; C073072:lodenosine; D016048:Dideoxyadenosine