BIOAVAILABILITY AND PHARMACOKINETIC PARAMETERS FOR 5-ETHYL-2'-DEOXYURIDINE

Pharmacokinetic parameters for 5-ethyl-2'-deoxyuridine (EDU) were determined following intravenous (iv) and oral (po) dosing in male Balb-e mice and iv dosing in male Sprague-Dawley rats. The concentrations of EDU in blood after 100 mg/kg iv bolus injections into mice and rats were consistent with a two compartment kinetic model. Based on this kinetic model, EDU showed a very short distribution half-life of 1.4 +/- 0.7 min in mice and 1.3 +/- 0.1 min in rats. The elimination half-life of EDU in rats following iv bolus injection, was substantially (18.5 +/- 1.0 min) shorter than that in mice (24.1 +/- 2.9 min). The mean residence time (MRT) of EDU was also substantially longer in mice (25.8 +/- 4.9 min) compared to rats (11.0 +/- 2.9 min). However, clearance of EDU was similar in both rats and mice. Although the biotransformation of EDU was similar in mice and rats, cleavage of the EDU glycoside bond was less extensive in mice than in rats. EDU showed a 49% bioavailability in mice after a 100 mg/kg po dose. The concentration of EDU in blood after a po dose provided the best fit to a one compartment model. The maximum blood concentration of EDU (C-max was 2.4 +/- 0.2 mu g/g of blood which attained 31.1 +/- 1.2 min (T-max) after a 100 mg/kg po dose. The AUC of 5-ethyluracil (EU) after a po dose of EDU was significantly higher (P < 0.05) than after an iv dose of EDU. This observation indicates that EDU undergoes degradation by phosphorylases present in the gastrointestinal tract and/or by presystemic metabolism.