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2 *-b-FLUORO-2 * , 3 *-DIDEOXYADENOSINE , LODENOSINE , IN RHESUS MONKEYS : PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS AND URINARY DISPOSITION 1

2*-b-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*-b-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. 29-b-Fluoro-29,39-dideoxyadenosine (lodenosine, F-ddA) 2 is an experimental anti-AIDS drug that is currently undergoing adult and pediatric Phase I clinical trials at the National Cancer Institute. This synthetic nucleoside was rationally designed to have improved chemical and enzymatic stability compared with 2 9,39-dideoxyadenosine (ddA), its parent compound, or ddA’s major metabolite, 2 9,39-dideoxyinosine (didanosine or ddI; Marquez et al., 1987). The addition of an electrophilic fluorine in the 29 position of the dideoxyribose ring (Fig. 1) yields a compound that is acid stable and has a greater than 90% reduction in adenosine deaminase (ADA)-catalyzed hydrolysis compared with ddA (Marquez et al., 1990). F-ddA is a reverse transcriptase inhibitor with a mechanism of action similar to other dideoxynucleoside analogs (didanosine, zidovudine, lamivudine, zalcitabine, and stavudine) currently approved by the Food and Drug Administration to treat HIV infection (Food and Drug Administration, 1998). F-ddA has two potential advantages over didanosine for treating AIDS. Its acid stability makes it a much better candidate for oral administration. Dog studies have demonstrated better bioavailability compared with didanosine (Stoltz et al., 1989). Also, F-ddA is more lipophilic than didanosine (Barchi et al., 1991), which may increase its ability to cross the blood-brain barrier. Penetration into the central nervous system (CNS) is critical in the treatment of patients with AIDS-related dementia (Gallo et al., 1987). F-ddA pharmacokinetics has been studied previously in other animals, and the CNS pharmacology of a variety of nucleoside analogs has been investigated in our nonhuman primate model, but F-ddA has not been studied in primates. In earlier studies, F-ddA, administered to rats as a 2-h i.v. infusion, was rapidly converted to 29b-fluoro-29,39dideoxyinosine (F-ddI) with a plasma-concentration time profile exhibiting biexponential elimination (Singhal et al., 1996). Other studies investigated the effects of halo-substitutions on the cerebrospinal fluid (CSF) penetration of 29,39-dideoxyguanosine (ddG) in monkeys. Administration of these halo-substituted compounds produced higher CSF to plasma ratios of ddG exposure compared with ddG administration; however, the prodrugs themselves were present at very low concentrations in the CSF so the mechanism of the improved penetration is unclear (Hawkins et al., 1995). The purpose of the present study was to determine the pharmacokinetics and urinary excretion of F-ddA and its major metabolite, F-ddI, in a nonhuman primate. In addition, the extent of penetration into the CNS was investigated using the ratio of CSF area under the 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. 2 Abbreviations used are: F-ddA, 29-b-fluoro-29,39-dideoxyadenosine; ddA, 29,39-dideoxyadenosine; ddI, 29,39-dideoxyinosine; ADA, adenosine deaminase; CNS, central nervous system; ddG, 29,39-dideoxyguanosine; CSF, cerebrospinal fluid; F-ddI, 29-b-fluoro-29,39-dideoxyinosine; AUC, area under the curve; MRT, mean residence time; PNP, purine nucleoside phosphorylase; DMSO, dimethyl