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Potency of the Effect of D-Stereoisomer of Aminoglutethimide on Adrenal and Extraadrenal Steroidogenesis^*

Division of Endocrinology, Department of Medicine, and The Specialized Cancer Research Center, The Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine Hershey, Pennsylvania 17033

Address requests for reprints to: Dr. E. Samojlik, Department of Medicine, Endocrinology Division, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033.

The racemic form of aminoglutethimide (DL-AG) inhibits several steroid biosynthetic steps, including cholesterol to pregnenolone conversion, the C-11, C-18, and C-21 hydroxylations, and the peripheral aromatization of androstenedione to estrone. Recent data suggested that the D-stereoisomer possesses most of the inhibitory activity. To evaluate the potency of the D-stereoisomer of AG, we measured estrone (E₁), estradiol (E₂), androstenedione (⁴-A), and dehydroepiandrosterone sulfate (DHEA-S) in postmenopausal patients with breast carcinoma during the administration of either the D or DL form of AG. In response to 1000 mg DL-AG and 40 mg hydrocortisone (HC) daily, E, fell from basal plasma levels of 46.5 ± 19.1 to 8.9 ± 1.1 pg/ml. Similarly, the concentrations of E₂, ⁴-A, and DHEA-S were also suppressed by DL-AG and HC. When patients were then switched to 450 mg D-AG, the levels of E₁, ⁴-A, and DHEA-S were suppressed to the same extent as with 1000 mg DL-AG. With respect to E2, a slight but significantly greater reduction (P < 0.05) occurred in patients treated with 450 mg D-AG than in those treated with 1000 mg DL-AG. NO greater inhibition was observed in response to the administration of 900 or 1440 mg D-AG daily. The bioavailabilities of the DL- and D-AG preparations were similar, as determined by measurements of drug levels in plasma.

These data demonstrate that the potency of 450 mg D-AG equals that of 1000 mg of the DL racemic form in suppressing the estrogens, DHEA-S, and androstenedione. Consequently, a regimen of 450 mg D-AG and HC could be used in patients to reduce drug-related toxicity.

^* This work was supported in part by National Cancer Institute Contract N01-CB-53851 and Grant 1-P30-CA-18450 from the National Cancer Institute, DHEW, Bethesda, MD.

Received January 7, 1980.

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