Levin Stuart, McMahon Ellen, John-Baptiste Annette, Bell Rosonald R
Takeda Global Research and Development, Deerfield, Illinois 60015, USA.
Toxicol Pathol. 2013 Feb;41(2):271-9. doi: 10.1177/0192623312468516. Epub 2012 Dec 12.
Eplerenone (Inspra) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not.
依普利酮（Inspra）是一种醛固酮受体拮抗剂，已被批准用于治疗高血压以及心肌梗死后的心力衰竭。体外受体结合和反式激活研究表明，与其他甾体受体（糖皮质激素、雄激素和孕激素受体）相比，依普利酮对盐皮质激素受体具有高选择性。临床前口服依普利酮最敏感的脱靶效应是犬前列腺萎缩。当依普利酮剂量≥15 mg/kg/天持续给药13周或更长时间时，可观察到剂量相关的前列腺萎缩。犬前列腺效应的未观察到不良反应水平（NOAEL）为5 mg/kg/天。最大效应在13周时出现，即使经过1年的每日治疗，这种萎缩也是可逆的。另一项研究表明，经直肠超声证实有依普利酮诱导的前列腺萎缩的犬精液量略有减少，但对性欲、精液蛋白含量、精子活力、每日精子生成量或附睾精子转运时间没有与化合物相关的影响。研究了前列腺效应的四种可能机制：（1）抑制睾酮合成和分泌；（2）抑制5α-还原酶，即前列腺内将睾酮转化为活性更高的生长因子双氢睾酮（DHT）的酶；（3）雄激素受体的竞争性拮抗作用；（4）醛固酮对5α-还原酶的抑制作用或雄激素受体的竞争性拮抗作用，在用依普利酮治疗的犬中醛固酮水平升高。这些研究的数据支持了依普利酮超药理浓度下对雄激素受体的阻断作用。另一种盐皮质激素阻滞剂螺内酯在体内和体外均比依普利酮具有更强的抗雄激素活性，并且在人类中具有众所周知的临床显著抗雄激素作用，而依普利酮则没有。
