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.

Abstract

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.

• Authors: T Kawaguchi, S Fukushima, Y Hayashi, M Kaneko, M Nakano
• Journal: Cancer research (Cancer Res) Vol. 48 Issue 15 Pg. 4179-83 (Aug 01 1988) ISSN: 0008-5472 [Print] United States
• PMID: 2839289 (Publication Type: Journal Article)

Chemical References

• Floxuridine
• Fluorodeoxyuridylate
• 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine
• Iodized Oil
• Pentosyltransferases
• Pyrimidine Phosphorylases
• Esterases

Topics

• Animals
• Esterases (metabolism)
• Floxuridine (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics)
• Fluorodeoxyuridylate (metabolism)
• Hepatic Artery
• Infusions, Intra-Arterial
• Iodized Oil
• Liver (enzymology)
• Liver Neoplasms, Experimental (metabolism)
• Male
• Pentosyltransferases (metabolism)
• Pyrimidine Phosphorylases
• Rabbits
• Tissue Distribution