Accumulation of 5-Ethyl-2′-deoxyuridine and its 5,6-Dihydro Prodrugs in Murine Lung and its Potential Clinical Application

Abstract

Abstract The accumulation of 5-ethyl-2′-deoxyuridine (EDU), (–)-trans-(5S, 6S)-5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2′-deoxyuridine [(5S, 6S)-BMEDU], (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2′-deoxyuridine [(5R, 6R)-BMEDU], (+)-trans-(5.R, 6R)-5-bromo-5-ethyl-6-ethoxy-5, 6-dihydro-2′-deoxyuridine (BEEDU), (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5′-O-valeryl-2′- deoxyuridine (VBEEDU) and (+)-trans-(5R, 6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-3′-5′-di-O-valeryl-2′-deoxyuridine (DVBEEDU) in lung and other tissues was investigated in male Balb-C mice following intravenous injection of the corresponding 4-14C-labelled compounds. EDU showed a rapid distribution into liver and lung immediately after injection, and the overall levels of radioactivity in blood, liver and lung were similar. The distribution of radioactivity in lung after injection of [4-14C](5S, 6S)-BMEDU and [4–14C](5R, 6R)-BMEDU were substantially different from one another and also from that of [4-14C]EDU. The radioactivity level present in lung samples after injection of both [4-14C](5S, 6S)-BMEDU and [4-14C](5R, 6R)-BMEDU was substantially higher than that in blood samples. Radioactivity levels present in lung samples taken at 18 min after injection of [4-14C]BEEDU were significantly higher (P < 0·05) than those for liver and blood samples. Although the radioactivity present in lung samples after injection of [4-14C]VBEEDU was significantly higher (P < 0·05) than those of liver and blood samples, [4-14C]VBEEDU did not provide a higher radioactivity level in lung samples than did [4-14C]BEEDU. The level of radioactivity in lung samples following injection of [4-14C]DVBEEDU was also higher than that of blood samples. EDU undergoes glycosidic bond cleavage to form EU in lung following intravenous injection into Balb-C mice. The concentrations of EDU and 5-ethyluracil (EU) following intravenous injection of EDU, and its prodrugs BEEDU and VBEEDU, were quantitated in lung and blood samples. In contrast to lung samples, EU was not detected in blood samples at 120 min post injection of EDU. The concentrations of both EDU and EU in lung tissues after injection of BEEDU and VBEEDU were substantially higher than those in blood samples.