The pharmacokinetics of probenecid were examined following single 0.5-, 1.0-, and 2.0-g oral doses to healthy male volunteers. Doses were administered following overnight fast, according to a randomized design. Plasma levels of probenecid were determined by high-pressure liquid chromatography (HPLC), using sulfamethazine as the internal standard. Mean peak probenecid levels of 35.3, 69.6, and 148.6 micrograms/ml were obtained at 3-4 hr following the 0.5-, 1.0-, and 2.0-g doses, respectively. Probenecid levels from the 0.5- and 1.0-g doses declined in apparent monoexponential fashion, with mean elimination half-lives of 4.2 and 4.9 hr. Interpretation of the 2.0-g data by a kinetic model incorporating first-order elimination resulted in a plasma drug half-life of 8.5 hr. When first-order elimination was replaced by a Michaelis-Menten-type function, the mean value of the resulting Vm/Km ratios was 0.20, equivalent to a plasma drug half-life [0.693/(Vm/Km)] of 3.8 hr. Plasma probenecid curves from all three dosages were successfully fitted to the saturable elimination model using nonlinear regression and numerical integration routines. The results suggest that probenecid elimination may be saturable at therapeutic dose levels.