title: A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity.
abstract: OBJECTIVE
  Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5-fluorouracil (5-FU) to 5-fluoro-5,6-dihydrouracil (5-FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5-FU and 5-FDHU pharmacokinetics, predisposing patients to the development of severe 5-FU-associated toxicity. Our objectives were to avoid severe 5-FU toxicities in patients with greatly impaired 5-FU and 5-FDHU pharmacokinetics after the administration of a reduced test dose of 5-FU and to investigate possible 5-FU or 5-FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5-FU chemotherapy.
  
  
  METHODS
  Pharmacokinetics of 5-FU/5-FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5-FU, 250 mg/m2, 2 weeks before starting the planned 5-FU treatment of 370 mg/m2 plus l-folinic acid, 100 mg/m2, for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria.
  
  
  RESULTS
  The 5-FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5-FU/5-FDHU pharmacokinetics (ie, 5-FU half-life [t(1/2 beta)] >5 hours, 5-FU total body clearance [CL(TB)] <1 L x h(-1) x m(-2), and 5-FDHU time to reach maximum plasma concentration [t max] > or = 45 minutes); they were excluded from 5-FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5-FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 +/- 2.18 h x microg/mL (mean +/- SD), maximum plasma concentration (Cmax) of 16.78 +/- 8.61 microg/mL, and t(1/2 beta) of 0.16 +/- 0.15 hour, whereas the CL(TB) was 65.67 +/- 31.86 L x h(-1) x m(-2). The 5-FDHU plasma profile showed a Cmax value of 3.64 +/- 1.94 microg/mL, whereas the t max value was 26.63 +/- 10.06 minutes, with an AUC value of 3.71 +/- 1.90 h x microg/mL. The PBMC DPD activity was 202.15 +/- 141.14 pmol 5-FDHU x min(-1) x mg(-1) protein (95% confidence interval, 165-239.3 pmol 5-FDHU x min(-1) x mg(-1) protein). A significant correlation between 5-FU AUC and 5-FDHU AUC was found (r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5-FDHU AUC (r = 0.328, P = .0121) and 5-FDHU Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU t max values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea (P = .0323 and P = .0138, respectively; chi-square test).
  
  
  CONCLUSIONS
  This study suggests a successful approach for preventing severe or life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy. g.bocci@med.unipi.it
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Cecilia
authors.initials: C
authors.lastname: Barbara
authors.forename: Francesca
authors.initials: F
authors.lastname: Vannozzi
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Melosi
authors.forename: Gemma
authors.initials: G
authors.lastname: Barsanti
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D016014:Linear Models; D008297:Male; D008875:Middle Aged
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil