The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer

Abstract

The disposition kinetics of a new 5-fluorouracil prodrug, 5'-deoxy-5-fluorouridine (5'dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5'dFUR (2 and 4 g.m-2) on separate days. Plasma concentrations of 5'dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l.min-1) but no apparent change in renal clearance (0.32 to 0.29 l.min-1) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5'dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.