Vol. 27, Issue 10, 1128-1132, October 1999

2'--Fluoro-2',3'-dideoxyadenosine, Lodenosine, in Rhesus Monkeys: Plasma and Cerebrospinal Fluid Pharmacokinetics and Urinary Disposition¹

Jeri S. Roth, Cynthia M. McCully, Frank M. Balis, David G. Poplack, and James A. Kelley

Laboratory of Medicinal Chemistry, Division of Basic Sciences (J.S.R., J.A.K.) and Pediatric Oncology Branch, Division of Clinical Sciences (C.M.M., F.M.B.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Hematology-Oncology Service, Texas Childrens Hospital (D.G.P.), Houston, Texas

2'--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'--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.