RT Journal Article
SR Electronic
T1 2′-β-Fluoro-2′,3′-dideoxyadenosine, Lodenosine, in Rhesus Monkeys: Plasma and Cerebrospinal Fluid Pharmacokinetics and Urinary Disposition
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1128
OP 1132
VO 27
IS 10
A1 Jeri S. Roth
A1 Cynthia M. McCully
A1 Frank M. Balis
A1 David G. Poplack
A1 James A. Kelley
YR 1999
UL http://dmd.aspetjournals.org/content/27/10/1128.abstract
AB 2′-β-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′-β-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. U.S. Government