title: Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs.
abstract: Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, South Korea.
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Baek
authors.forename: Byung-Yo
authors.initials: BY
authors.lastname: Lee
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005467:Floxuridine / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000493:pharmacokinetics*; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D053719:Tandem Mass Spectrometry; D014529:Uridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D002214:Capsules; D007202:Indicators and Reagents; D005467:Floxuridine; C001943:5-fluorouridine; D005472:Fluorouracil; C025034:doxifluridine; D014529:Uridine
references.citation: Biochem Pharmacol. 1986 Aug 1;35(15):2461-5
references.pmid: 3741455
references.citation: Br J Cancer. 2003 Oct 20;89(8):1486-92
references.pmid: 14562021
references.citation: J Toxicol Sci. 2011 Aug;36(4):411-22
references.pmid: 21804305
references.citation: Cancer Res. 1980 Sep;40(9):3333-8
references.pmid: 6253060
references.citation: Anticancer Res. 2003 May-Jun;23(3B):2559-64
references.pmid: 12894541
references.citation: Farmaco. 1997 Feb;52(2):71-81
references.pmid: 9181686
references.citation: J Vet Intern Med. 1994 May-Jun;8(3):240-3
references.pmid: 8064664
references.citation: Eur J Clin Pharmacol. 1987;32(4):411-8
references.pmid: 3609119
references.citation: Eur J Cancer. 1980 Apr;16(4):427-32
references.pmid: 6447071