Selective accumulation/retention of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8) and sustained release of its active metabolites, 5-fluoro-2'-deoxyuridine (FdUrd) and 5-fluoro-2'-deoxyuridylate (FdUMP), in the rabbit hepatoma (VX-2) were achieved following intrahepatic arterial administration of FdUrd-C8 solution in Lipiodol. Though no significant difference in the FdUrd-C8 levels among the tumor and nontumorous liver was observed immediately after administration, slower elimination of FdUrd-C8 from the tumor (t 1/2 = 15.8 h) than that from nontumorous sites (t 1/2 = 3.8-4.2 h) resulted in selective retention of FdUrd-C8 (17- to 157-fold) in the tumor. Selectively higher levels of FdUrd and FdUMP in the tumor were also achieved (5- to 35-fold) and kept for 72 h after administration. The selective accumulation was also demonstrated in radioactivity distribution after administration of [6-3H]-FdUrd-C8. The ratio of radioactivity in the tumor divided by that in the blood (T/B ratio) was in a range of 870 to 5400 during a 15- to 1440-min period after administration. A trace of radioactivity was found in the stomach, duodenum, kidneys, and bone marrow. Roles of activation and deactivation enzymes on the selective distribution of FdUrd-C8 were also investigated. Esterase activity, which is responsible for the regeneration of FdUrd from FdUrd-C8, was relatively low in the tumor before administration and gradually increased after administration. Phosphorylase activity, which is related to phosphorolytic cleavage of FdUrd, in the tumor was about 3/5 as much as that in the nontumorous liver. These enzyme activities seem to play limited roles in the selective accumulation/retention and regeneration of the drug.