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Medline ® Abstract for Reference 81

of 'Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management'

81
TI
Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule.
AU
Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, Monahan BP, Quinn MG, Cliatt J, Nguyen D, Grollman F, Thomas RR, McQuigan EA, Wilson R, Takimoto CH, Grem JL
SO
Cancer Chemother Pharmacol. 2003 Jul;52(1):79-85. Epub 2003 Apr 18.
 
PURPOSE: To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV).
METHODS: A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m(2) to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m(2) on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m(2) on day 2 weekly for 3 of 4 weeks.
RESULTS: Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m(2) per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to>5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-beta-alanine was not detectedwhile urinary excretion was reduced to<1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound.
CONCLUSIONS: Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase.
AD
National Cancer Institute-Navy Medical Oncology, Cancer Therapeutics Branch, Center for Cancer Research, National Naval Medical Center, Bethesda, MD 20889-5105, USA.
PMID