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 language | English |
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Pages (from-to) | 625-632 |
Number of pages | 8 |
Journal | Anticancer Research |
Volume | 31 |
Issue number | 2 |
State | Published - Feb 2011 |
Externally published | Yes |
Keywords
- 5-Fluorouracil
- CDHP
- DPD
- FBAL
- FT
- Gimeracil
- Phase I
- Reversible dihydropyrimidine dehydrogenase
- S-1
- Solid tumors
- Tegafur