The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37 degrees C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. The findings suggest the possibility of pulmonary clearance of 5-FU.