Dukes M
Cancer Metabolism Endocrine Department, Zeneca Pharmaceuticals, Macclesfield, UK.
Oncology. 1997;54 Suppl 2:6-10. doi: 10.1159/000227748.
The predictive value of test results in animals when selecting a compound for potential therapeutic human use depends upon the relevance of the animal model to the human disease and the comparative pharmacokinetics of the compound in animals and man. The development of the aromatase inhibitor, anastrozole (Arimidex), illustrates the importance of these factors. In postmenopausal women with breast cancer, aromatase activity in the peripheral tissues is the main source of oestrogen for tumour growth. Only one form of the human enzyme is known, which is not subject to strong feedback control. Inhibition of aromatase therefore simply reduces oestrogen production. This situation is mimicked by assays of acute inhibition of ovulation in rats, chronic inhibition of androstenedione-induced uterine hypertrophy in sexually immature rats, and chronic inhibition of peripheral aromatase in monkeys. In all these assays, maximum anastrozole activity was consistently achieved at an oral dose of about 0.1 mg/kg, and the clearance half-life of 7-16 h indicated that once-daily dosing would be possible in humans. The clearance half-life in postmenopausal women is about 50 h, and with once-daily dosing the dose of anastrozole required for maximal inhibition is 1 mg/day. The rat 7,12-dimethylbenzanthracene tumour model, in contrast, is supported by ovarian oestrogen and chronic inhibition provokes positive feedback loops that try to restore oestrogen production, masculinise the animals and decrease the clearance half-life of anastrozole. Higher doses (10 mg/kg) of anastrozole are therefore needed. Variations in the dose of aromatase inhibitor required in different models, therefore, can be explained in terms of pharmacokinetics and do not reflect the effectiveness of anastrozole as an aromatase inhibitor.
在选择具有潜在治疗用途的化合物时，动物试验结果的预测价值取决于动物模型与人类疾病的相关性以及该化合物在动物和人类体内的比较药代动力学。芳香酶抑制剂阿那曲唑（瑞宁得）的研发就说明了这些因素的重要性。在绝经后乳腺癌女性中，外周组织中的芳香酶活性是肿瘤生长雌激素的主要来源。已知人类芳香酶只有一种形式，且不受强反馈控制。因此，抑制芳香酶只会减少雌激素的产生。这种情况在大鼠急性排卵抑制试验、性未成熟大鼠中雄烯二酮诱导的子宫肥大慢性抑制试验以及猴子外周芳香酶慢性抑制试验中都有体现。在所有这些试验中，口服剂量约为0.1mg/kg时始终能达到阿那曲唑的最大活性，7 - 16小时的清除半衰期表明人类每日给药一次是可行的。绝经后女性的清除半衰期约为50小时，每日给药一次时，达到最大抑制所需的阿那曲唑剂量为1mg/天。相比之下，大鼠7,12 - 二甲基苯并蒽肿瘤模型依赖卵巢雌激素，慢性抑制会引发正反馈回路，试图恢复雌激素产生，使动物雄性化并缩短阿那曲唑的清除半衰期。因此需要更高剂量（10mg/kg）的阿那曲唑。所以，不同模型中所需芳香酶抑制剂剂量的差异可以从药代动力学角度进行解释，并不反映阿那曲唑作为芳香酶抑制剂的有效性。
