Pharmacokinetics of 5-fluorouracil infusions in the rat: Comparison with man and other species

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Abstract
Saturable elimination of 5-FU is exhibited in rats during constant infusions. Over the range of 3–480 mg/m2/h, total-body clearance of 5-FU decreases from 600 ml/min/m2 to less than 90 ml/min/m2. Previously published values for catabolism of 5-FU by rat hepatocytes can be used to simulate the plasma concentrations of 5-FU that were measured over this range of infusions. The qualitative pattern of nonlinear pharmacokinetics for 5-FU is similar in rats, dogs, monkeys, and humans. However, there are major quantitative differences in total-body clearance values, expressed in terms of surface area (ml/min/m2) or as a fraction of cardiac output. Rat and monkey have substantially lower 5-FU clearance values than dog and man. Although 5-FU clearance values were similar in dogs and humans, total body clearance values for thymidine are 18-fold higher in humans than in dogs. The selection of an appropriate animal model to pursue the clinical observations of high total body clearance of pyrimidines remains uncertain.