Geisler J, Lundgren S, Berntsen H, Greaves J L, Lønning P E
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
J Clin Endocrinol Metab. 1998 Aug;83(8):2687-93. doi: 10.1210/jcem.83.8.5035.
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).
氨鲁米特（AG）是迄今为止在乳腺癌患者中使用最广泛的芳香化酶抑制剂。在商业上，AG（奥鲁米坦）以消旋体（DL-AG）形式提供。先前的研究表明，AG的立体异构体（D-AG和L-AG）在抑制不同细胞色素P-450依赖性酶的亲和力和效力上有很大差异，其中D-AG是强效芳香化酶抑制剂。DL-AG除了是一种芳香化酶抑制剂外，还已知可增强血浆硫酸雌酮（E1S）的代谢。在本研究中，我们在一项涉及12名绝经后乳腺癌患者的交叉研究中，比较了D-AG（每日500毫克）和DL-AG（每日1000毫克）对血浆雌激素水平以及在注射[14C]E1和[3H]E1S后测定的雌酮（E1）和E1S清除率的影响。用DL-AG和D-AG治疗后，血浆E1S分别降至治疗前水平的18.6%和15.0%，而在用DL-AG治疗期间E1和雌二醇E2水平分别降至治疗前水平的18.6%和23.4%，在用D-AG治疗期间分别降至17.7%和23.4%。因此，两种治疗方案对所有测量的雌激素的抑制程度相似。在用DL-AG和D-AG治疗期间，E1S的清除率分别从治疗前的平均5.9升/小时增加到14.0升/小时和10.0升/小时（比较两种治疗状态，P < 0.05），而E1S的产生率在用DL-AG时从治疗前的1.44纳摩尔/小时降至0.64纳摩尔/小时，用D-AG时降至0.36纳摩尔/小时（比较治疗值，P < 0.05）。这些发现与AG的D型和L型均可能提高E1S清除率的假设一致。与D-AG相比，DL-AG治疗期间雌激素产生率较高这一发现可能反映了雌激素前体雄烯二酮的血浆水平升高（在用D-AG和DL-AG治疗期间，雄烯二酮的平均水平分别为2.54纳摩尔/升和1.27纳摩尔/升；P < 0.05）。
