Abstract
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.
Footnotes
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Send reprint requests to: Jeri S. Roth, Laboratory of Medicinal Chemistry, Bldg. 37, Room 5C-02, 37 Convent Drive, National Institutes of Health, Bethesda, MD 20892. E-mail:rothj{at}dc37a.nci.nih.gov
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↵1 Some of the data in this paper were originally presented at the 1992 Pittsburgh Conference & Exposition on Analytical Chemistry and Applied Spectroscopy, March 11, 1992, New Orleans, LA, and at the Sixteenth International Symposium on Column Liquid Chromatography, June 16, 1992, Baltimore, MD.
- Abbreviations used are::
- F-ddA
- 2′-β-fluoro-2′,3′-dideoxyadenosine
- ddA
- 2′,3′-dideoxyadenosine
- ddI
- 2′,3′-dideoxyinosine
- ADA
- adenosine deaminase
- CNS
- central nervous system
- ddG
- 2′,3′-dideoxyguanosine
- CSF
- cerebrospinal fluid
- F-ddI
- 2′-β-fluoro-2′,3′-dideoxyinosine
- AUC
- area under the curve
- MRT
- mean residence time
- PNP
- purine nucleoside phosphorylase
- DMSO
- dimethyl sulfoxide
- Received February 17, 1999.
- Accepted June 16, 1999.
- U.S. Government
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