In Vivo and in Vitro Pharmacological Studies of Aminoglutethimide as an Aromatase Inhibitor1

Use of steroid biosynthesis inhibitors to suppress estrogen production is a logical strategy in the treatment of women with hormone-dependent breast cancer. The clinical availability of aminoglutethimide as an inhibitor of cytochrome P-450-mediated steroid hydroxylations prompted study of the precise pharmacological and biochemical effects of this drug. Pharmacokinetic studies revealed that aminoglutethimide alters its own metabolic clearance rate as well as that of dexamethasone, a synthetic glucocorticoid. The metabolic clearance rates of other steroids such as hydrocortisone, medroxyprogesterone acetate, androstenedione, and estrone are not altered by aminoglutethimide. These findings led to development of a practical regimen of escalating aminoglutethimide dosage in combination with hydrocortisone for treatment of patients with breast carcinoma. Further studies focused upon the biochem ical mechanism of estrogen suppression with aminoglutethi mide. In vivo, isotopie kinetic data demonstrated that amino glutethimide inhibits peripheral aromatase by 95 to 98% in postmenopausal women. In vitro experiments indicated that aminoglutethimide can effectively block aromatase directly in human breast tumors as well. With respect to relative potency, aminoglutethimide is a 10-fold more potent aromatase inhibitor than is testololactone but is less potent than are 4-hydroxyandrostenedione and several brominated androstenedione deriv atives. Taken together, these studies suggest that aminoglu tethimide blocks estrogen production at three sites in women with breast carcinoma: the adrenal cortex, extraglandular pe ripheral tissues containing aromatase, and breast carcinoma tissue itself. Introduction While AG2 was initially introduced in the United States as an anticonvulsant, subsequent clinical observations demonstrated its potent inhibitory effects on adrenal steroid biosynthesis (3, 7, 9, 14). By binding to cytochrome P-450 complexes, AG blocks the cholesterol side-chain cleavage enzyme as well as the C-21, C-11, and C-18 steroid hydroxylases (4, 7, 9, 10, 23). Cash et al. (3) first conceived the use of AG as a form of "medical adrenalectomy" for treatment of metastatic breast carcinoma in patients who were otherwise candidates for sur gical adrenalectomy. Griffiths era/. (8) later reported beneficial effects in 3 of 9 such women treated. Our group then studied the use of AG, focusing primarily on its precise pharmacological effects and mechanism of action. Since other antiepileptic 1 Presented at the Conference "Aromatase: New Perspectives tor Breast Cancer," December 6 to 9, 1981, Key Biscayne. Fla. Supported in part by National Cancer Institute Contract CB-NCI-53851, The Core Endocrine Labora tory, and Specialized Cancer Center Grant 1P30 CA18450, awarded by the National Cancer Institute, Department of Health, Education, and Welfare. 2 The abbreviations used are: AG, aminoglutethimide; MCR, metabolic clear ance rate. agents such as phénobarbital were known to alter drug metab olism (2, 5), we first examined the effect of AG on the metabolic clearance of several synthetic and endogenous steroids as well as on its own metabolism. Stimulated by the studies of Thomp son and Siiteri (21 , 22), we then evaluated the ability of AG to block aromatase in vivo and in vitro and its relative potency compared to other aromatase inhibitors (1 8). Our data demonstrated that AG accelerates its own metab olism as well as that of dexamethasone but does not alter the metabolic clearance of hydrocortisone, medroxyprogesterone acetate, androstenedione, and estrone. When given with re placement hydrocortisone, AG blocks estrogen synthesis at 3 sites: the adrenal cortex; extraglandular peripheral tissues containing aromatase; and breast carcinoma tissue itself. MATERIALS AND METHODS