A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil

M. Wasif Saif, L. S. Rosen, K. Saito, C. Zergebel, L. Ravage-Mass, D. S. Mendelson

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19 Scopus citations

Abstract

The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone. Patients and Methods: Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks. Results: A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m2. Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p≤0.0007 for AUC0.inf, AUC0-last, and C max of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p<0.0001 for all comparisons). Following both single-and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP. Conclusion: Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.

Original languageEnglish
Pages (from-to)625-632
Number of pages8
JournalAnticancer Research
Volume31
Issue number2
StatePublished - Feb 2011
Externally publishedYes

Keywords

  • 5-Fluorouracil
  • CDHP
  • DPD
  • FBAL
  • FT
  • Gimeracil
  • Phase I
  • Reversible dihydropyrimidine dehydrogenase
  • S-1
  • Solid tumors
  • Tegafur

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