The pharmacokinetics of sulfisoxazole and sulfanilamide were studied in control rats and in rats treated for 5 days with a daily 100 mg/kg ip dose of phenobarbital. These drugs represent the organic anionic and nonionized drugs, respectively, whose nonmicrosomal enzymatic metabolisms were unstimulated by phenobarbital. Sulfisoxazole showed the characteristics of a two-compartment open model. However, its biological half-life and the apparent distribution volume of the central compartment were significantly lower and the intercompartmental transport rate constants and the urinary excretion rate constant were significantly greater, in phenobarbital treated rats than in control rats. The apparent steady-state distribution volume of sulfisoxazole was smaller in the phenobarbital treated rats at the 90% confidence level. Sulfanilamide showed characteristics of a one-compartment model in both the control and phenobarbital treated rats, but none of the pharmacokinetic parameters of the compound in the phenobarbital treated rats were significantly different from those in the control rats.