Single-Dose and Steady-State Pharmacokinetics of Aminoglutethimide

Abstract

The oral pharmacokinetics of aminoglutethimide were determined in 17 patients receiving the drug therapeutically. The absorption of aminoglutethimide after oral intake was almost complete as judged by recovery of radio-labelled drug in the urine. The plasma half-life of the drug was markedly reduced (mean 43%) during multiple-dose administration as compared with a single dose, but only a moderate increase in total clearance (mean 26.9%) was observed. This finding was consistent with a significant reduction (mean 29.2%) in apparent volume of distribution (Vd) occurring during prolonged treatment. These alterations in drug distribution could also be demonstrated after a drug-free interval of 96 hours during treatment. The reduction in apparent volume of distribution could not be explained by altered plasma protein binding of aminoglutethimide, as evaluated by equilibrium dialysis experiments.

Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients

“…The excellent bioavailability of PyG found in this study compares well with that of aminoglutethimide (Lonning et al, 1985), and demonstrates the effectiveness of oral dosing. PyG has previously been shown to exhibit non-linear pharmacokinetics after a single oral dose of 1000 mg (Haynes et al, 1991).…”

Alterations in the Metabolism of Oestrogens During Treatment with Aminoglutethimide in Breast Cancer Patients

“…The aminoglutethimide concentrations measured in plasma in this study were consistent with earlier findings (3 to 22 mgfL) during long term treatment (250mg 4 times/day) [Lenning et al 1985] for all patients in phase 3. Therefore, the dif- ference in oestrogen disposition between short and long term aminoglutethimide treatment is probably not related to a subtherapeutic plasma aminoglutethimide concentration following short term dosage.…”

“…Firstly, glucocorticoids were also administered to the patients investigated in protocol I, who showed no change in their oestrogen disposition after short term aminoglutethimide treatment. Secondly, cortisol plasma concentrations will remain within the normal range in most patients receiving hydrocortisone acetate 25mg twice daily during long term aminoglutethimide treatment, as aminoglutethimide imposes an inhibitory effect on endogenous cortisol synthesis in the adrenal cortex (Lenning et al 1985). Thirdly, the 3 patients investigated in protocol III received no glucocorticoids when investigated in phase 2.…”

The influence of CGS 16949A on peripheral aromatisation in breast cancer patients

“…will have steady state plasma drugs concentrations varying between 2 and lO ng ml-' or 8 and 40 nM (Lipton et al, 1990). Steady state plasma concentrations of aminoglutethimide in patients receiving 250 mg or 1000 mg daily are about 400 and 1600-fold higher respectively (Murray et al, 1979;L0nning et al, 1985;Stuart-Harris et al, 1985). While in vitro studies have suggested CGS 16949A to be 200 and 400 times more potent than aminoglutethimide (Steele et'al., 1987), any comparison of plasma drug levels should be interpreted with care, as no information considering tissue drug levels are available.…”