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Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion.

Abstract：

:Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5'-dFUR and 5-fluorouracil (5-FU) when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5'-dFUR and 5-FU at steady state for each infusion rate enabled the estimation of 5'-dFUR renal (ClR) and nonrenal (ClNR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m2 per 120 h. The lowest dose given over 24 h was 0.25 g/m2, and the highest was 5 g/m2. Steady-state plasma levels of 5'-dFUR ranged from 167 to 6,519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5'-dFUR metabolism; steady-state plasma levels of 5'-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5'-dFUR renal clearance. The mean (+/- SD) ClR of 5'-dFUR was 108.9 +/- 53.6 ml/min per m2 (range, 45.7-210 ml/min per m2), and the ClNR was 728 +/- 181 ml/min per m2 (range, 444-1,119 ml/min per m2). Renal clearance comprised 13% of the total 5'-dFUR clearance. The mean renal clearance of 5-FU was 100.8 +/- 48.6 ml/min per m2 (range, 23.5-198 ml/min per m2). There was considerable interpatient variability in 5'-dFUR renal and nonrenal clearance, even at the same dose level. We concluded that the administration of 5'-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Reece PA,Olver IN,Morris RG,Bishop JF,Guentert TW,Hill HS,Hillcoat BL

doi

10.1007/BF00684885

subject

Has Abstract

pub_date

1990-01-01 00:00:00

pages

274-8

issue

4

eissn

0344-5704

issn

1432-0843

journal_volume

25

pub_type

杂志文章

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