Cancer Chemother Pharmacol (1990) 25 : 274- 278 ancer hemotherapy and harmacology 9 Springer-Verlag 1990 Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion* Phillip A. Reece 1, Ian N. Olver 2, Raymond G. Morris 1, James F. Bishop 2, Theodore W. Guentert 3, Heather S. Hill 1, and Brian L. Hillcoat 2 1 Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Adelaide, South Australia, 5011, Australia 2 Peter MacCallum Cancer Institute, 481 Little Lonsdale Street, Melbourne, Victoria, 3000, Australia 3 Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., P. O. Box, CH-4002 Basel, Switzerland Summary. 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 in- fusion 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 (CIR) and nonrenal (CINR) clearance and 5-FU renal clearance. A total of 28 patients with histo- logically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m 2 per 120 h. The lowest dose given over 24 h was 0.25 g/m ~, and the highest was 5 g/m 2. 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 in- creased 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) C1R of 5'-dFUR was 108.9 + 53.6 ml/min per m 2 (range, 45.7-210 ml/min per m2), and the C1NR was 728 + 18t ml/min per m 2 (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 m 2 (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. therapeutic indices than 5-fluorouracil (5-FU) [4, 7]. 5'-dFUR is a prodrug of 5-FU [2, 6, 11] that releases 5-FU in turnout cells as a result of the action of intracellular pyrimidine nucleoside phosphorylases [9]. Higher con- centrations of 5-FU are released in tumours than in nor- mal tissues [10], probably as a result of higher concentra- tions of pyrimidine phosphorylase in tumour tissues. By contrast, slower conversion of 5'-dFUR to 5-FU in bone marrow has been reported [1, 7]. 5'-dFUR metabolism is saturable and is associated with a fall in clearance of the drug as the dose is increased [3, 5, 8, 13, 15]. The initial decline in levels after a short in- fusion of 5'-dFUR indicated zero-order elimination, which eventually became first-order below concentrations of approximately 50 mM(~12 ~g/ml). The decline in 5-FU plasma levels paralleled the decline in 5'-dFUR leves, sug- gesting that 5-FU formation was rate-limiting [13]. Dihydrofluorouracil (5-FUH2) formation or transport also appeared to be saturated under these conditions. The aim of the present study was to determine the dis- position of 5'-dFUR and 5-FU when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased step- wise every 24 h. This method of administration was chosen to avoid the high peak plasma levels and toxicity as- sociated with shorter infusion regimens. Although depend- ent on the dose and rate of administration, the half-lives of 5'-dFUR and 5-FU are relatively short, and steady-state levels are readily attained with a 24-h infusion of 5'- dFUR. 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 and nonrenal clearance and 5-FU renal clearance. The dose dependency of 5'-dFUR disposition with this administration schedule could then be examined. Introduction Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR, Ro 21- 9738) is a fluoropyrimidine that was synthesized in the search for new cytostatic antimetabolites with greater * This study was supported by a grant from F. Hoffmann-La Roche, Basel, Switzerland Offprint requests to: Dr. P. A. Reece, 2 Edgecombe Road, St. Ives, NSW, 2075 Australia Patients and methods Patients. A total of 28 patients with histologically proven malignancy were studied (Table 1). To be eligible for the study, patients must have been considered refractory to conventional therapy or had a tumour for which no estab- lished effective therapy existed. At least 3 weeks must have elapsed since prior chemotherapy (6 weeks in the case of mitomycin C or the nitrosoureas). Liver and renal function tests must have been shown to be normal prior to entry into the study. All patients were older than 18 years of age and gave informed consent before proceeding with the