Kang Keon W, Kim Yoon G
Department of Pharmacology, College of Medicine, Dankook University, San 29, Anseo-Dong, Chonan-Si, Choungnam 330-714, Republic of Korea.
J Clin Pharmacol. 2008 Dec;48(12):1430-7. doi: 10.1177/0091270008323262. Epub 2008 Oct 1.
This study aimed to investigate the bioequivalence of a test formulation of tibolone with the marketed reference formulation in 24 young healthy female volunteers. Tibolone is a synthetic steroid hormone for menopausal women. Volunteers were treated with the 2 formulations of tibolone (total dose of active ingredient 2.5 mg) according to a 2 x 2 crossover design with a 1-week washout period. Plasma concentrations of 3alpha- and 3beta-hydroxytibolone, which are major metabolites of tibolone, were assayed in timed samples over a 24-hour period with a validated gas chromatography/mass spectrometry (GC/MS) method that had a lower limit of quantification of 0.5 ng/mL. The reference and test formulations gave a mean 3alpha-hydroxytibolone C(max) of 5.0 and 5.2 ng/mL, respectively, and a mean 3beta-hydroxytibolone C(max) of 16.4 and 16.5 ng/mL, respectively. The mean AUC(t) of 3alpha-hydroxytibolone was 24.7 and 24.3 ng h/mL, whereas the mean AUC(t) of 3beta-hydroxytibolone was 57.6 and 54.8 ng h/mL for the test and reference formulations, respectively. The authors did not find significant differences in pharmacokinetic parameters between the 2 formulations, but metabolite formation was different from reports in postmenopausal women. The authors therefore measured the effects of estradiol on the expression of the tibolone-metabolizing enzymes, from the aldo-keto reductase (AKR1C) family, using HepG2 cell (human hepatoma cells) and MCF-7 cell (human breast cancer cells). Estradiol increased mRNA levels of AKR1C1, AKR1C2, and AKR1C3 and protein levels of total AKR1C in HepG2 cells. Estradiol selectively enhanced levels of AKR1C2 mRNA in MCF-7 cells. Thus, changes in the major metabolites of tibolone might result from changes in AKR1C family expression by patient estrogen status.
本研究旨在调查替勃龙试验制剂与市售参比制剂在24名年轻健康女性志愿者中的生物等效性。替勃龙是一种用于绝经后女性的合成甾体激素。志愿者按照2×2交叉设计接受两种替勃龙制剂（活性成分总剂量2.5mg）治疗，洗脱期为1周。采用经过验证的气相色谱/质谱（GC/MS）方法，在24小时内定时采集样本，测定替勃龙的主要代谢产物3α-和3β-羟基替勃龙的血浆浓度，该方法的定量下限为0.5ng/mL。参比制剂和试验制剂的3α-羟基替勃龙的平均C(max)分别为5.0和5.2ng/mL，3β-羟基替勃龙的平均C(max)分别为16.4和16.5ng/mL。试验制剂和参比制剂的3α-羟基替勃龙的平均AUC(t)分别为24.7和24.3ng·h/mL，而3β-羟基替勃龙的平均AUC(t)分别为57.6和54.8ng·h/mL。作者未发现两种制剂在药代动力学参数上有显著差异，但代谢产物的形成与绝经后女性的报道不同。因此，作者使用HepG2细胞（人肝癌细胞）和MCF-7细胞（人乳腺癌细胞）测量了雌二醇对替勃龙代谢酶（来自醛糖酮还原酶（AKR1C）家族）表达的影响。雌二醇增加了HepG2细胞中AKR1C1、AKR1C2和AKR1C3的mRNA水平以及总AKR1C的蛋白水平。雌二醇选择性地提高了MCF-7细胞中AKR1C2 mRNA的水平。因此，替勃龙主要代谢产物的变化可能是由于患者雌激素状态导致AKR1C家族表达的改变。
