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Selective Accumulation of 3',5'-Dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8) and Sustained Release of Its Active Metabolites in VX-2 Rabbit Hepatoma following Intraarterial Administration of FdUrd-C8 Solution in Lipiodol

Department of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-02 and Bio-Medical Research Institute, Teijin Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191 [T. K.]; and Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860 [S. F., Y. H., M. K., M. N.], Japan

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 = 15.8 h) than that from nontumorous sites (t = 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.

¹ Present address: Department of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-02, Japan.

¹ To whom requests for reprints should be addressed.

Received 4/30/87. Revised 2/16/88. Accepted 5/ 5/88.