DeGregorio M W, Wurz G T, Taras T L, Erkkola R U, Halonen K H, Huupponen R K
Department of Internal Medicine, Cancer Center, University of California, Davis, Sacramento 95817, USA.
Eur J Clin Pharmacol. 2000 Sep;56(6-7):469-75. doi: 10.1007/s002280000176.
New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro- 1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies.
The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25-200 mg. Standard pharmacokinetic parameters were assessed.
In the single-dose study, time to reach peak concentration (tmax) ranged from 1.3 h to 4.0 h; peak concentration (Cmax) ranged from 15 ng/ml to 445 ng/ ml; and the estimated terminal elimination half-life (mean +/- SD; t1/2) was 24.8 +/- 7.0 h. In the repeated-dose study, tmax ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. Cmax ranged from 295 ng/ml to 1,043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t1/2 at all dose levels was 29.7 +/- 1.5 h (overall mean +/- SD). Strong linear correlations between the dose and Cmax and between the dose and the area under the curve were observed in both studies.
Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens.
新型选择性雌激素受体调节剂用于治疗和预防骨质疏松症、心血管疾病及乳腺癌，目前是深入研究的焦点。（脱氨基羟基）托瑞米芬（Z-2-[4-(4-氯-1,2-二苯基-丁-1-烯基)苯氧基]乙醇；FC-1271a）已被证明可在大鼠中预防骨吸收，同时对子宫无或仅有微弱的雌激素样作用，这使其成为预防骨质疏松症的良好候选药物。我们在此的目的是研究在两项I期研究中纳入的人体（脱氨基羟基）托瑞米芬的药代动力学。
第一项是对28名健康男性志愿者进行的单剂量、剂量递增研究。剂量范围为10毫克至800毫克。第二项研究在12周期间对40名健康的绝经后女性进行，她们接受了25 - 200毫克的重复口服剂量。评估了标准药代动力学参数。
在单剂量研究中，达峰时间（tmax）范围为1.3小时至4.0小时；峰浓度（Cmax）范围为15纳克/毫升至445纳克/毫升；估计的末端消除半衰期（平均值±标准差；t1/2）为24.8±7.0小时。在重复剂量研究中，6周时tmax范围为1.9小时至2.6小时，12周时为2.5小时至2.9小时。6周时Cmax范围为295纳克/毫升至1043纳克/毫升，12周时为25纳克/毫升至1211纳克/毫升。所有剂量水平的平均t1/2为29.7±1.5小时（总体平均值±标准差）。两项研究均观察到剂量与Cmax以及剂量与曲线下面积之间有很强的线性相关性。
我们的结果表明，（脱氨基羟基）托瑞米芬具有适合每日单次给药的药代动力学。因此，可以使用与其他激素替代治疗方案类似的每日一次给药方案，对易患骨质疏松症、心血管疾病和乳腺癌的女性预防性使用该药物进行测试。
