Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.