title: Hepatic fibrosis does not affect the pharmacokinetics of 5-fluorouracil in rats.
abstract: In the case of cancer chemotherapy for hepatocellular carcinoma, 5-fluorouracil (5-FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5-Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5-FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5-fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5-FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate-limiting enzyme in 5-FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5-FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5-FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs.
authors.affiliation: Department of Pharmacy, University of Miyazaki Hospital, and Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hidaka
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Tomomi
authors.initials: T
authors.lastname: Iwakiri
authors.forename: Manabu
authors.initials: M
authors.lastname: Okumura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arimori
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002251:Carbon Tetrachloride; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007261:Infusions, Intra-Arterial; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000964:Antimetabolites, Antineoplastic; D002251:Carbon Tetrachloride; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil