The Fate of 5-Trifluoromethyl-2′-deoxyuridine in Monkeys, Dogs, Mice, and Tumor-bearing Mice^1,2 Free

The metabolic fate of 5-trifluoromethyl-2′-deoxyuridine (F₃TdR) has been determined in dogs, monkeys, and tumor-bearing and normal mice. After a single intravenous dose, radioactivity leaves the blood of monkeys and dogs with a half-time of approximately 30 minutes. However, a fraction of the radioactivity remaining in the blood cannot be extracted with perchloric acid up to 24 hours after administration of the drug. Most of the dose (60–93%) is excreted in the urine by 24 hours as F₃TdR, trifluorothymine (F₃T), and 5-carboxydeoxyuridine or 5-carboxyuracil. There is no significant difference in rate or percent of excretion by monkeys which received over 90 doses of F₃TdR or by monkeys and dogs which received no F₃TdR prior to the radioactive dose. However, detailed analyses of all radioactive molecular species in the urine revealed a 4-fold species difference in the excretion of F₃TdR and F₃T by dogs and monkeys. The data indicate that monkeys convert F₃TdR to F₃T at 4–6 times the rate of dogs. This is consistent with the finding that monkeys can tolerate about 4–6 times the dose of F₃TdR as dogs. Less than one percent of the radioactivity is excreted in the feces or as radioactive carbon dioxide in the breath.

The tissues of dogs, monkeys and mice contain only 2–30 µg F₃TdR equivalents per gm 24 hours after an intravenous dose. However, a substantial fraction of that radioactivity is not extractable with perchloric acid. There seems to be a trend toward higher binding to tissues which are most damaged, such as bone marrow (dogs and monkeys), lymph nodes (dogs), and tumor (mice). Several lines of evidence indicate that the binding is covalent and primarily to protein. A reaction between F₃T and plasma constituents in vitro suggests that part or all of the binding reaction is nonenzymatic.