Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate in mice and dogs.

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate (2-F-araAMP) has been studied in mice and dogs after iv administration. Following injection of 40 mg/m2 into mice, serum levels of 2-F-araAMP fell, with apparent half-lives of 0.7 mins for the alpha phase and 21 mins for the beta phase. Rapid dephosphorylation of the compound resulted in high levels of the nucleoside, 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-araA), which disappeared from serum in two phases, with half-lives of 31 and 114 mins. 9-beta-D-Arabinofuranosyl-2-fluorohypoxanthine (2-F-araHx) was also present in serum. After administration of 500 mg/m2 of 2-F-araAMP to mice, the apparent half-lives for the parent compound were 2.5 and 27 mins. Serum levels of 2-F-araA fell, with apparent half-lives of 36 and 185 mins. Tissue distribution studies revealed that, in mice administered 40 mg/m2, the liver, kidney, and spleen contained the highest levels of 2-F-araAMP. For most tissues, elimination of 2-F-araAMP occurred exponentially but at a slower rate than in serum. As in serum, the major tissue metabolite was 2-F-araA; other metabolites identified were 2-F-araHx, 2-fluoroadenine (2-F-A), and polyphosphorylated derivatives of 2-F-araA. In mice dosed with 500 mg/m2, the tissue distribution of metabolites was similar, but the levels were about tenfold higher. With both doses, 2-F-araAMP, 2-F-araA, and 2-F-araHx were recovered in urine. In dogs administered 40 mg/m2, serum levels of 2-F-araAMP fell rapidly in an initial phase of 5 mins and in a second phase of 30 mins. As in mice, the major serum metabolite was 2-F-araA, which disappeared in two phases of 16 and 97 mins. After administration of 500 mg/m2 to dogs, the apparent half-lives for 2-F-araAMP in serum were 9 and 51 mins. For 2-F-araA, a single phase of disappearance of 89 mins was evident. In dog serum, as compared with mouse serum, a greater percentage of the administered compound was metabolized to 2-F-araHx. During 24 hrs following administration of either 40 or 500 mg/m2 of 2-F-araAMP to dogs, less than 2% of the dose was excreted in urine as unchanged drug. Approximately equal percentages of 2-F-araA and 2-F-araHx were recovered in urine after both doses. The levels of 2-F-A in urine comprised about 2% of the radioactivity after administration of either the low or the high dose. The studies demonstrate that 2-F-araAMP undergoes rapid dephosphorylation in both mice and dogs. Deamination of the dephosphorylated product is more rapid in dogs than in mice.