title: Circadian variation in plasma 5-fluorouracil concentrations during a 24 hour constant-rate infusion.
abstract: BACKGROUND
  Varying the rate of continuous intravenous infusions of 5-fluorouracil (5FU) chemotherapy over a 24-hour period has been reported to improve patient outcomes. It has been hypothesized that circadian variation in drug disposition is a contributing factor. We analyzed 5-FU concentrations during a 24-hour continuous 5-FU infusion.
  
  
  METHODS
  Sixty-four subjects with advanced malignancies including pancreatic, hepatocellular, colorectal as well as other epithelial malignancies and either abnormal hepatic or renal function were treated on a phase I and pharmacokinetic study of weekly 24-hour intravenous infusions of 5-FU and leucovorin. No other concomitant anticancer therapy was administered. Blood samples were collected every three hours from 61 subjects for measurement of plasma 5-FU during the first two weekly infusions.
  
  
  RESULTS
  After adjusting for differences in dose, elapsed time from start of infusion and infusion number (2 versus 1), mean 5-FU concentration was highest at 6 am and lowest at 3 pm, with an overall change in the mean from 3 pm to 6 am of +20 percent (95% CI = 12-28%). However, this variation in mean concentration associated with time of day was comparable in magnitude to the between-patient differences, within-patient differences between infusions, and the residual variation within infusion (coefficient of variation = 21%).
  
  
  CONCLUSIONS
  Our data show systematic variation by time of day in plasma concentrations of 5-FU administered at a constant rate over 24 hours, but it is small compared to the total variation in plasma concentration contributed by other sources. Circadian variation in men was more pronounced than in women.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. gfleming@medicine.bsd.uchicago.edu.|The University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue, Chicago, IL, 60637, USA. gfleming@medicine.bsd.uchicago.edu.|Committee on Clinical Pharmacology and Pharmacogenomics, 57th Street Box 11, Chicago, IL, 60637, USA. gfleming@medicine.bsd.uchicago.edu.|The University of Chicago Medical Center, 5841 S. Maryland Ave., MC 2115, Chicago, IL, 60637, USA. gfleming@medicine.bsd.uchicago.edu.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: Department of Public Health Sciences, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA. pschumm@rcg.bsd.uchicago.edu.
authors.forename: Philip
authors.initials: P
authors.lastname: Schumm
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. gfriberg@amgen.com.
authors.forename: Greg
authors.initials: G
authors.lastname: Friberg
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. mratain@medicine.bsd.uchicago.edu.|The University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue, Chicago, IL, 60637, USA. mratain@medicine.bsd.uchicago.edu.|Committee on Clinical Pharmacology and Pharmacogenomics, 57th Street Box 11, Chicago, IL, 60637, USA. mratain@medicine.bsd.uchicago.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. uchenna.njiaju@uchealth.org.
authors.forename: Uchenna O
authors.initials: UO
authors.lastname: Njiaju
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. richard.schilsky@asco.org.|The University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue, Chicago, IL, 60637, USA. richard.schilsky@asco.org.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002955:Leucovorin; D005472:Fluorouracil