title: Effects of a bolus injection of 5-fluorouracil on dihydropyrimidine dehydrogenase activity in rats receiving continuous infusion of 5-fluorouracil.
abstract: OBJECTIVE
  The options for improving the chemotherapeutic regimen consisting of bolus plus infusion of 5-fluorouracil (5-FU) include omitting the 5-FU bolus injection. We examined the effects of a 5-FU bolus injection on the activity of dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of 5-FU catabolism, in rats.
  
  
  METHODS
  The rats were divided into three groups, and then continuous infusion (50 mg/m(2)/h) for 4 h was started with a bolus injection of saline, 20 mg/kg 5-FU, or 60 mg/kg 5-FU. Plasma 5-FU, uracil (Ura), dihydrouracil (UH2) levels, and hepatic DPD activity were determined after administration of 5-FU.
  
  
  RESULTS
  The half-life after the end of the infusion (t 1/2, 4-8 h) of 5-FU in the rats given the bolus injection was significantly longer than in those that had been given saline, and it increased with increasing 5-FU bolus injection dosage (r = 0.801, p < 0.01). The plasma UH2/Ura ratio, an indirect biomarker of hepatic DPD activity, tended to be lower in the rats that had received a 5-FU bolus injection than in those that had not, and it remained low after infusion ended. The hepatic DPD activity in rats that had received a 5-FU bolus injection was significantly lower than in those that had not. Negative correlation was observed between DPD activity and bolus injection dosage (r = -0.691, p < 0.05).
  
  
  CONCLUSIONS
  A bolus injection suppresses hepatic DPD activity and its effects are dependent on dosage, resulting in slower elimination of 5-FU from the blood and contributing to long-term systemic exposure to 5-FU.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, 589-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan. sakaedat@mb.kyoto-phu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D007267:Injections; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-FU; Anti-cancer agent; Cancer chemotherapy; Dihydropyrimidine dehydrogenase; Pharmacokinetics; Rats