Journal article
Oral uracil and Ftorafur plus leucovorin : pharmacokinetics and toxicity in patients with metastatic cancer
Cancer chemotherapy and pharmacology, Vol.46(5), pp.351-356
2000
DOI: 10.1007/s002800000156
PMID: 11127938
Abstract
Purpose: To assess the pharmacokinetics of Ftorafur (tegafur, FT), 5-fluorouracil (5-FU), and uracil in 31 cancer patients who were enrolled in phase I studies of oral uracil and FT (UFT). The correlation between pharmacokinetic parameters and toxic effects of UFT was evaluated. Methods: Uracil and FT were orally administered in a 4:1 molar ratio at FT doses of 200-400 mg/m2 per day. Patients also received leucovorin at 150 mg/day. Daily doses were divided into three doses and administered at 8-h intervals for 28 consecutive days. Plasma FT concentrations were measured by high-performance liquid chromatography, and plasma 5-FU and uracil concentrations were determined using gas chromatography-mass spectrometry. National Institutes of Health Common Toxicity Criteria were used for assessment of toxicity. Results: The concentrations of FT, 5-FU, and uracil showed wide interpatient variations. Maximum plasma concentrations (Cp(max)) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t(1/2β)) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC(0-6h)) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (Cl(T)) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vd(ss)) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t(1/2α)) and an apparent elimination half-life (t(1/2β)) of 0.3-1.3 h and 4.9-7.0 h, respectively. The AUC(0-6h) of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t(1/2α) of 0.2-0.5 h and the level quickly returned to the endogenous level. The AUC(0-6h) for uracil ranged from 605 to 3764 (ng/ml)h, the Cl(T) ranged from 3225 to 7748 ml/min, and the Vd(ss) ranged from 341 to 1354 l. The Cp(max) and AUC(0-6h) of both FT and uracil were significantly correlated with FT doses (P-values of 0.0244 and 0.0112) and with uracil doses (P-values of 0.0346 and 0.0083), respectively. In addition to interpatient variations, intrapatient variations were also observed in six patients who had pharmacology studies done on days 1 and 26 ± 2 at the same study dose. We found that the repeated treatment with UFT caused cumulative increases in the values of Cp(max), C(trough), and AUC(0-6h) of FT and 5-FU. The major toxic effects observed were diarrhea and nausea and vomiting. The occurrence of these toxic effects correlated significantly with the Cp(max) and AUC(0-6h) of 5-FU. Conclusions: The pharmacology studies showed that FT and uracil were readily absorbed orally and that FT was rapidly converted to 5-FU. The preliminary findings suggest that determination of plasma levels of 5-FU after oral administration of UFT may help predict subsequent toxic effects.
Details
- Title: Subtitle
- Oral uracil and Ftorafur plus leucovorin : pharmacokinetics and toxicity in patients with metastatic cancer
- Creators
- Dah H HO - The University of Texas MD Anderson Cancer CenterWendy Covington - The University of Texas MD Anderson Cancer CenterJun Kuritani - Taiho PharmaceuticalTomohisa Hayakawa - Taiho PharmaceuticalNita Brown - The University of Texas MD Anderson Cancer CenterSan N Lin - Center for Human Toxicology, Biomedical Polymer Bldg., 20 S. 2030 E., Suite 490, Salt Lake City, UT 84112, USA, USRichard Pazdur - The University of Texas MD Anderson Cancer CenterYuang-Yi Huo - The University of Texas MD Anderson Cancer CenterPatrick J Creaven - Roswell Park Cancer InstituteYoucef M Rustum - Roswell Park Cancer InstituteNeal J Meropol - Fox Chase Cancer CenterYvonne Lassere - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- Cancer chemotherapy and pharmacology, Vol.46(5), pp.351-356
- Publisher
- Springer
- DOI
- 10.1007/s002800000156
- PMID
- 11127938
- ISSN
- 0344-5704
- eISSN
- 1432-0843
- Language
- English
- Date published
- 2000
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359890102771
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