Oral uracil and Ftorafur plus leucovorin: pharmacokinetics and toxicity in patients with metastatic cancer

Autor: Tomohisa Hayakawa, Dah H. Ho, San N. Lin, Yvonne Lassere, Jun Kuritani, N. S. Brown, Richard Pazdur, Neal J. Meropol, Youcef M. Rustum, Patrick J. Creaven, Wendy Covington, Yuang Yi Huo
Rok vydání: 2000
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 46:351-356
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s002800000156
Popis: 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 (Cpmax) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t1/2β) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC0–6h) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (ClT) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vdss) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t1/2α) and an apparent elimination half-life (t1/2β) of 0.3–1.3 h and 4.9–7.0 h, respectively. The AUC0–6h of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t1/2α of 0.2–0.5 h and the level quickly returned to the endogenous level. The AUC0–6h for uracil ranged from 605 to 3764 (ng/ml)h, the ClT ranged from 3225 to 7748 ml/min, and the Vdss ranged from 341 to 1354 l. The Cpmax and AUC0–6h 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 Cpmax, Ctrough, and AUC0–6h 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 Cpmax and AUC0–6h 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.
Databáze: OpenAIRE
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