Santen R J, Demers L M, Lynch J, Harvey H, Lipton A, Mulagha M, Hanagan J, Garber J E, Henderson I C, Navari R M
Division of Endocrinology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
J Clin Endocrinol Metab. 1991 Jul;73(1):99-106. doi: 10.1210/jcem-73-1-99.
CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.
CGS 16949A（盐酸法倔唑）是一种强效的细胞色素P450介导的类固醇生成抑制剂，低剂量时可阻断芳香化酶，但在较高浓度时会阻断其他生物合成步骤。最近的研究表明，在比阻断芳香化酶所需浓度稍高的情况下，该药物可抑制11β-羟化酶、皮质酮甲基氧化酶-II以及脱氧皮质酮向皮质酮的转化。基于I期研究，我们推测，如果使用足够低剂量的CGS 16949A，可能会实现对芳香化酶的相对选择性抑制。一项针对54名绝经后转移性乳腺癌女性的II期研究，考察了低剂量CGS 16949A对雌激素、盐皮质激素和糖皮质激素分泌的影响。根据我们之前的剂量递增方案研究，选择了两种给药方案和两个剂量水平。给予1.8 - 4mg CGS 16949A，每日两次或每日三次给药方案，血浆雌酮、雌二醇和硫酸雌酮以及尿雌酮和雌二醇均同等程度下降。同位素动力学研究表明，雄烯二酮向雌酮的转化速率下降了84%，降至0.40±0.07%（每日接受1.8 - 4mg CGS 16949A的患者）。采用这三种方案，在12周的观察期内，醛固酮和皮质醇的基础水平没有显著变化。临床检查、血浆电解质和尿钠/钾比值均未提示有盐皮质激素缺乏的生物学证据。然而，与治疗前值相比，每个剂量水平的促肾上腺皮质激素（ACTH）刺激的皮质醇浓度均有所降低。尽管如此，在97%的情况下，峰值反应超过550nmol/L，或基础值与峰值的差值为190nmol/L或更大。这可能反映了11β-羟化酶受到抑制，因为给予CGS 16949A后，基础和ACTH刺激的11-脱氧皮质醇水平均升高。雄烯二酮和17α-羟孕酮在药物治疗后也呈现上升趋势。ACTH刺激的醛固酮水平比皮质醇受到的抑制程度更大，这可能反映了II型皮质酮甲基氧化酶受到阻断。总体而言，结果表明，每日剂量为1.8 - 2mg的CGS 16949A可有效阻断芳香化酶，且不会对皮质醇或醛固酮的生物合成产生具有临床意义的抑制作用。因此，该药物在不补充糖皮质激素或盐皮质激素的情况下可能可以安全使用。
