title: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase.
abstract: OBJECTIVE
  To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule.
  
  
  METHODS
  Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/ m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmaco-kinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3.
  
  
  RESULTS
  Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122% +/- 40% (mean +/- SD), the terminal half-life (t1/2 beta) was 4.5 +/- 1.6 hours, the apparent volume of distribution (V beta) was 21.4 +/- 5.9 L/ m2, and the systemic clearance (Clsys) was 57.6 +/- 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85.
  
  
  CONCLUSIONS
  The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD.
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: S P
authors.initials: SP
authors.lastname: Khor
authors.forename: A A
authors.initials: AA
authors.lastname: Adjei
authors.forename: M
authors.initials: M
authors.lastname: Doucette
authors.forename: T
authors.initials: T
authors.lastname: Spector
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: S E
authors.initials: SE
authors.lastname: Sartorius
authors.forename: D A
authors.initials: DA
authors.lastname: Noe
authors.forename: J A
authors.initials: JA
authors.lastname: Hohneker
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D042943:Dihydrouracil Dehydrogenase (NADP); D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D010088:Oxidoreductases / Q000187:drug effects*; D014018:Tissue Distribution; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil