Kochak G M, Mangat S, Mulagha M T, Entwistle E A, Santen R J, Lipton A, Demers L
Department of Clinical Pharmacokinetics and Disposition, Ciba-Geigy Corp., Ardsley, New York 10502.
J Clin Endocrinol Metab. 1990 Nov;71(5):1349-5. doi: 10.1210/jcem-71-5-1349.
In this dose-ranging phase I study, the relationship between in vivo androgen to estrogen conversion kinetics and plasma concentrations of fadrozole was investigated in postmenopausal women receiving therapy with this aromatase inhibitor. Patients received ascending doses, ranging from 0.3-8 mg fadrozole twice daily, each for a period of 2 weeks. Drug kinetics and endocrine effects were evaluated specifically for the 2- and 8-mg twice daily treatment regimens. The in vivo activity of the drug was demonstrated by the suppression of estrone and estradiol biosynthesis from testosterone and androstenedione, respectively. The drug inhibitory constant, KI, for the estrone synthetic pathway, was 3.0 ng/mL (13.4 nmol/L) and was of similar magnitude as that determined under in vitro conditions. The KI for the estradiol synthetic pathway was 5.3 ng/mL (23.7 nmol/L). The disparity between KI values may indicate that the two pathways are not equivalent in terms of their inhibition by fadrozole. Pharmacokinetic data demonstrated tha the drug was rapidly absorbed after oral dosing, with peak plasma concentrations achieved in median times of 1 and 2 h, respectively, for the 2- and 8-mg twice daily treatment regimens. The average half-life and oral clearance values were 10.5 h and 621 mL/min, respectively. Oral clearance was independent of dose.
在这项剂量范围的I期研究中，在接受这种芳香化酶抑制剂治疗的绝经后妇女中，研究了体内雄激素向雌激素转化动力学与法倔唑血浆浓度之间的关系。患者接受递增剂量，每天两次，剂量范围为0.3 - 8mg法倔唑，每次为期2周。专门针对每日两次2mg和8mg的治疗方案评估了药物动力学和内分泌效应。该药物的体内活性分别通过抑制睾酮和雄烯二酮生成雌酮和雌二醇的生物合成来证明。雌酮合成途径的药物抑制常数KI为3.0 ng/mL（13.4 nmol/L），与体外条件下测定的数值大小相似。雌二醇合成途径的KI为5.3 ng/mL（23.7 nmol/L）。KI值之间的差异可能表明这两条途径在法倔唑抑制方面并不等同。药代动力学数据表明，口服给药后药物吸收迅速，对于每日两次2mg和8mg的治疗方案，血浆浓度分别在1小时和2小时的中位时间达到峰值。平均半衰期和口服清除率值分别为10.5小时和621 mL/分钟。口服清除率与剂量无关。
