Summary
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±1.7h (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 μg/ml x h. The total clearance rate was 5.5±0.91/h and the volume of distribution was 80±11 l. 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 μg/ml, respectively. After 1 month of treatment, however, AG plasma levels of 6–7 and 4–5 μg/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.
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Abbreviations
- AG:
-
aminoglutethimide
- AAG:
-
N-acetylaminoglutethimide
- G:
-
glutethimide
- HPLC:
-
high-performance liquid chromatography
- SD:
-
standard deviation
- SE:
-
standard error of the mean
- AUC:
-
area under the concentration versus time curve
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Miller, A.A., Miller, B.E., Höffken, K. et al. Clinical pharmacology of aminoglutethimide in patients with metastatic breast cancer. Cancer Chemother. Pharmacol. 20, 337–341 (1987). https://doi.org/10.1007/BF00262588
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DOI: https://doi.org/10.1007/BF00262588