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Distribution, Metabolism, and Excretion of 1-(2-Fluoro-2-deoxy-ß-D-arabinofuranosyl)thymine and 1-(2-Fluoro-2-deoxy-ß-D-arabinofuranosyl)-5-iodocytosine¹

Laboratories of Pharmacology [F. S. P., A. F., T-C. C., P. M. V.] and Organic Chemistry [T-L. S., K. A. W., J. J. F.], Sloan-Kettering Institute for Cancer Research, New York, New York 10021

1-(2-Fluoro-2-deoxy-ß-D-arabinofuranosyl)thymine (FMAU) and 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)-5-iodocytosine (FIAC) are potent inhibitors of the replication of herpesviruses; FMAU is chemotherapeutically effective against murine leukemias which have acquired resistance to 1-ß-D-arabinofuranosylcytosine. We describe the synthesis of [2-¹⁴C]FMAU which we have used to compare with [2-¹⁴C]FIAC in studies of pharmacological disposition and metabolic fate after giving each of the substances i.v. or p.o. Most of the radioactivity of these substances is excreted in urine within 24 hr after administration in mice and rats. During the same period, the recovery in feces and respiratory CO₂ is, for each, less than 5%. Biliary excretion from the common bile duct of rats is low, 2 to 4% of dose during the first 5 hr after i.v. injection. Chromatographic analysis of 24-hr urine collections after giving FMAU reveals that most of the radioactivity in mouse and rat urine is present as unchanged drug. Mouse urine also contains significant amounts of three unidentified metabolites of FMAU; these have also been detected in mouse plasma and in rat urine. Chromatographic analyses of plasma and urine samples from mice and rats given FIAC show that this substance is substantially transformed by deamination into a major metabolite, 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)-5-iodouracil. Deiodinated metabolites have also been detected, namely, 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)cytosine and 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)uracil. Radioactivity in extracerebral organs of rats receiving labeled FIAC or FMAU is, within 10 min after i.v. injection, maximal and in concentrations equivalent to or higher than in plasma. Maximal concentrations after p.o. doses are reached within 30 to 60 min. At later times, rates of decrease in extracerebral organs parallel those in plasma. Half-lives after p.o. doses are higher than after i.v. doses. Penetration of radioactivity into rat brain is rapid, and the ratio of brain to plasma concentrations increases steadily to over 0.5 during the first 6 hr after dosing. Substantially greater concentrations appear in brain after FMAU than after FIAC. Studies of radioactivity remaining in various portions of the gut of rats given p.o. doses of the labeled drugs suggest that most of the absorption takes place from the stomach or upper end of the small intestine. In dogs, the rates of renal clearance of FMAU and FIAC are less than 20% that of creatinine when plasma concentrations are 10-fold greater than that inhibiting herpesvirus replication in vitro by 90%. Nearly all of the radioactivity excreted in dog urine during the first 24 hr after i.v. [2-¹⁴C]FMAU consists of unchanged drug. After [2-¹⁴C]FIAC, the 24-hr urinary radioactivity is composed primarily of unchanged drug and the deiodinated metabolites, 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)cytosine and 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)uracil; only trace amounts of the deaminated product, 1-(2-fluoro-2-deoxy-ß-D-arabinofuranosyl)-5-iodouracil, were detected.

¹ Supported in part by National Cancer Institute Grants CA-08748, CA-18856, and CA18601 and by the Elsa U. Pardee Foundation.

² To whom requests for reprints should be addressed.

Received 1/31/83. Accepted 5/ 5/83.

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