The pharmacology of aminoglutethimide (AG) was studied in two subsequent trials without hydrocortisone supplementation. A total of 79 patients with metastatic breast cancer entered the study, and their plasma and urine samples were analyzed by high-performance liquid chromatography (HPLC). Thirty evaluable patients with a median age of 57 years (range, 37-79) were treated with the standard dose of 1000 mg/day, and 37 evaluable patients with a median age of 59 years (range, 35-79) received 500 mg/day. The median follow-up in the two groups was 5 months (range, 1-16) and 4 months (range, 1-21), respectively. After the first oral dose of 500 mg, peak plasma concentrations of AG were observed 1-4 h after administration in 15 patients. The elimination half-life was 10.1 +/- 1.7 h (mean +/- SD) after initial dosage; it decreased significantly to 6.9 +/- 1.2 h after 8 weeks of treatment. The area under the curve of AG concentrations was 92.5 +/- 14.2 micrograms/ml x h. The total clearance rate was 5.5 +/- 0.9 1/h and the volume of distribution was 80 +/- 111. About 23% of the drug was excreted unchanged in the urine. The major metabolite, N-acetyl-AG (AAG), had the same half-life as AG. A comparison on day 7 of treatment revealed that doses of 1000 and 500 mg yielded AG plasma concentrations of 9.0 +/- 1.2 and 4.5 +/- 0.5 micrograms/ml, respectively. After 1 month of treatment, however, AG plasma levels of 6-7 and 4-5 micrograms/ml were observed, respectively. A 50% reduction of dose, therefore, resulted in only 30% lower AG levels during continuous treatment. Apparently, the induction of metabolism is of greater importance in standard-dose than in lower dose treatment. The plasma concentrations of AG did not bear a relationship to the clinical response.