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Influence of Dexaminoglutethimide, an Optical Isomer of Aminoglutethimide, on the Disposition of Estrone Sulfate in Postmenopausal Breast Cancer Patients¹

Department of Oncology, Haukeland University Hospital (J.G., H.B., P.E.L.), N-5021 Bergen; and the Department of Oncology, University Hospital Trondheim (S.L.), N-7006 Trondheim, Norway; and Chiroscience Ltd. (J.L.G.), Cambridge, United Kingdom

Address all correspondence and requests for reprints to: P. E. Lønning, Department of Oncology, Haukeland University Hospital, Department of Oncology, N-5021 Bergen, Norway.

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E₁S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E₁) and E₁S clearance rates, determined after the injection of [¹⁴C]E₁ and [³H]E₁S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E₁S to 18.6% and 15.0% of pretreatment levels, whereas E₁ and estradiol E₂ levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E₁S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E₁S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E₁S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).

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