Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors
Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors
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DOI：
10.1016/s0960-0760(01)00126-1
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发表时间：
2001-12-01
影响因子：
4.1
通讯作者：
Dowsett，M
中科院分区：
文献类型：
--
作者：
Boeddinghaus，IM;Dowsett，M
芳香化酶抑制剂（AIs）的临床开发一直受到临床药理学研究的密切指导。在开发的早期阶段，研究重点是剂量相关的药理学有效性和特异性。最近的注意力已经给予了代谢的变化，人工智能引起的，特别是关于他们的潜在用途在早期乳腺癌和预防设置。已使用血浆雌激素测定法研究了药理学有效性，但主要雌激素（E1和E2）对比较第三代抑制剂：阿那曲唑、来曲唑、阿司美坦没有帮助。所有这三种化合物抑制全身芳香化> 96%。最近，我们已经确定，在临床使用的剂量下，来曲唑比阿那曲唑具有更大的抑制作用。这种更完全的抑制被E1S的显著更大的抑制所抵消。一个广泛的内分泌研究小组已经表明，这些化合物在其临床剂量下基本上具有完全的特异性。阿司美坦的一个轻微的雄激素作用是通过显着抑制性激素结合球蛋白（SHBG）。目前许多研究正在收集脂质和骨生物标志物数据。来曲唑和他莫昔芬之间存在药代动力学相互作用，联合应用可降低来曲唑的循环水平。阿那曲唑和来曲唑与他莫昔芬联合给药时，对他莫昔芬的血浆浓度均无任何影响。
The clinical development of aromatase inhibitors (AIs) has been closely guided by clinical pharmacological investigations. During the early phases of development studies were focused on dose-related pharmacological effectiveness and specificity. More recently attention has been given to the metabolic changes which AIs elicit, with particular regard to their potential use in early breast cancer and the prophylactic setting. Pharmacological effectiveness has been studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not helpful in comparing the third generation inhibitors: anastrozole, letrozole, exemestane. All three of these compounds suppress whole body aromatisation by >96%. Most recently, we have established that significantly greater inhibition is achieved by letrozole than anastrozole at their clinically used dosages. This more complete inhibition is paralleled by significantly greater suppression of E1S. A broad panel of endocrine investigations has indicated that these compounds have essentially complete specificity at their clinical dosages. A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG). Lipid and bone biomarker data are being collected in many current studies. A pharmacokinetic interaction has been established between letrozole and tamoxifen, whereby reduced circulating levels of letrozole are found with combined application. Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it.