PHARMACOKINETICS AND BIOAVAILABILITY OF 5-ETHYL-2'-DEOXYURIDINE AND ITS NOVEL (5R,6R)-5-BROMO-6-ETHOXY-5,6-DIHYDRO PRODRUGS IN MICE

The pharmacokinetics and oral (po) bioavailability of 5-ethyl-2'-deoxy uridine (EDU) and its novel 5,6-dihydro prodrugs bromo-5-ethyl-6-ethox y-5,6-dihydro-2'-deoxyuridine (BEEDU) and -6-ethoxy-5,6-dihydro-5'-O-v aleryl-2'-deoxyuridine (VBEEDU) were determined in male Balb/C mice fo llowing intravenous and pc administration of a 0.4 mmol/kg dose. EDU w as eliminated from blood with a half-life of 35.2 +/- 4.2 min. The mea n residence time (MRT) and the area under the blood vs. time curve (AU C) for EDU after iv injection were 45.1 +/- 11.7 min and 1.7 +/- 0.2 m u mol.g(-1).min, respectively. EDU showed a 49% bioavailability in mal e Balb/C mice. The pharmacokinetic parameters and bioavailability of E DU were improved significantly upon administration of the 5,6-dihydro prodrugs BEEDU or VBEEDU. The AUC of EDU after a 0.4 mmol/kg iv dose o f BEEDU was 2.1 +/- 0.3 mu mol/g(-1).min, which is substantially highe r than that after iv injection of EDU. The half-life and MRT of EDU we re increased to 251.9 +/- 30.2 min and 352.0 +/- 91.5 min, respectivel y, after injection of BEEDU. The po bioavailabiIity of EDU, after admi nistration of BEEDU, was increased almost 2-fold (81%), compared with that of EDU (49%). The AUC of EDU after iv injection of VBEEDU was 1.8 +/- 0.2 mu mol.g(-1).min. The half-life and MRT of EDU, the active me tabolite of VBEEDU, were 106.0 +/- 23.2 min and 157.0 +/- 40.8 min, wh ich are substantially higher than those for EDU after administration o f EDU. The bioavailability of EDU after po administration of VBEEDU wa s 89%. 5-Ethyluracil was the major metabolite of EDU after both iv and po administration of EDU or its 5-bromo-6-ethoxy-5,6-dihydro prodrugs (BEEDU and VBEEDU). The ratio of the AUC(5-ethyluracil)/AUC(EDU) afte r po administration of EDU (1.8) was significantly higher than that af ter an iv injection (0.7). This ratio was also higher after administra tion of either BEEDU or VBEEDU. These observations may indicate that b oth EDU and its 5,6-dihydro prodrugs BEEDU and VBEEDU undergo some gly cosidic bond cleavage in the gastrointestinal tract and/or hepatic pre systemic degradation upon first-pass extraction and before entering th e general circulation.