Seventh Annual Report Summary Published

Serum aminoglutethimide (AG) and N-acetylaminoglutethimide (NAG) concentrations were measured by high pressure liquid chromatography (HPLC) in 24 postmenopausal women with advanced breast cancer receiving increasing doses of oral AG. Patients received 62.5mg b.d., 125mg b.d., 250mg b.d., and 500mg b.d. of AG alone, and 500mg b.d. of AG combined with hydrocortisone (HC) 20mg b.d. Dose was increased at monthly intervals. Each dose increment was accompanied by a significant rise in serum AG and NAG levels (P<0.05). The addition of HC to the dose of 500mg b.d. of AG did not alter serum AG or NAG concentrations significantly. Although serum AG and NAG levels appeared to increase linearly with dose, serum NAG increased significantly more slowly, leading to a fall in the NAG:AG ratio during therapy. The NAG :AG ratio appeared to stabilise only after about 6 months of treatment. Aminoglutethimide (AG), in a dose of 1 g daily combined with hydrocortisone (HC), is effective in the treatment of advanced postmenopausal breast cancer (Smith et al., 1978; Harris et al., 1982); Santen et al., 1982) and has been assumed to act as a "medical adrenalectomy". Adrenal suppression is achieved principally through inhibition of the desmolase enzyme system (Kahnt & Neher, 1966; Cash et al., 1967) responsible for the conversion of cholesterol to pregnenolone. However, AG also inhibits the peripheral aromatase enzyme system In vitro studies suggest that aromatase inhibition is achieved by lower doses of AG than necessary for desmolase inhibition thus, aromatase inhibition rather than adrenal suppression may be the underlying mechanism of oestrogen suppression by AG. For this reason, and as the side effects of AG have been reported to be dose-related (Murray et al., 1979), several investigators have recently assessed the use of low dose AG, without a glucocorticoid as a method of ostrogen suppression (Stuart-Harris et al. To date, there are only limited data concerning the metabolism and pharmacokinetics of AG. After oral administration of 0.1-I.Og of AG, 35-54% of the dose is excreted unchanged in the urine within 48 hours (Douglas & Nicholls, 1965, 1972). N-acetylaminoglutethimide (NAG) has been identified as the major metabolite, and 4-25% of an oral dose of AG is excreted as urinary NAG within 48 h. Acetylation is phenotype dependent with significantly higher levels of NAG achieved by fast acety-lators (Coombes et al., 1980). Peak plasma AG levels of 5.6-6.3 4ugml-1 have been observed 0.7-1.5h after 500mg AG given to healthy volunteers …