Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model.
BACKGROUND
Hepatic intra-arterial infusion chemotherapy of 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUDR) has been a treatment option for liver metastasis from colorectal cancer. However, an optimal administration schedule of 5-FU is still controversial. This study was conducted to evaluate a suitable schedule from the viewpoint of 5-FU metabolites and related enzymes.


METHODS
5-FU was infused into the hepatic artery of rabbits having hepatic deposits of VX2 tumor cells in a daily dose of 1, 4, or 8 mg/kg using various schedules. 5-FU, Thymidylate synthase (TS), TS inhibition rate (TSIR), and the amount of fluoro-RNA (F-RNA) were measured.


RESULTS
A high concentration of 5-FU was detected in the tumors of the group that was administered a dose of 8 mg/kg. TSIR in the tumor was about two-fold higher in the rabbits that were administered a total dose of 8 mg/kg than in those that were administered doses of 4 mg/kg or less. F-RNA, ranging from 27 to 36 ng/mg RNA, was detected in the tumor of the rabbits that were administered a total dose of 8 mg/kg. No difference was observed between the short period and the continuous administration schedules of rabbits that were administered a dose of 8 mg/kg of 5-FU. However, DNA synthesis inhibition in normal hepatic tissue was more dependent on the administration schedule than on the total dose of 5-FU because TSIR was significantly higher with shorter periods of drug administration.


CONCLUSIONS
Intermittent bolus administration of large doses of 5-FU might cause more severe hepatic impairment than continuous administration. These results suggest that hepatic intra-arterial infusion of 5-FU should be administered continuously for liver metastasis, although further experiments including a longer administration period of 5-FU are required.
Sadahiro
Sotaro
S
Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan. sadahiro@is.icc.u-tokai.ac.jp
Suzuki
Toshiyuki
T
Ishikawa
Kenji
K
Tanaka
Yoichi
Y
Masuda
Takahisa
T
Nakamura
Tomoki
T
Yasuda
Seiei
S
Makuuchi
Hiroyasu
H
Murayama
Chieko
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005467:Floxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D011817:Rabbits; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D005472:Fluorouracil