Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR (Council of Scientific and Industrial Research), Lucknow 226001, Uttar Pradesh, India.
J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Oct 1;879(27):2845-51. doi: 10.1016/j.jchromb.2011.07.036. Epub 2011 Aug 2.
Tamoxifen is the agent of choice for the treatment of estrogen receptor-positive breast cancer. Tamoxifen is a substrate of P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A, and biochanin A (BCA) is an inhibitor of P-gp and CYP3A. Hence, it could be expected that BCA would affect the pharmacokinetics of tamoxifen. In the present study we have developed and validated a simple, sensitive and specific LC-ESI-MS/MS method for the simultaneous quantification of tamoxifen and its metabolite 4-hydroxytamoxifen with 100 μL rat plasma using centchroman as an internal standard (IS). Tamoxifen, 4-hydroxytamoxifen and IS were separated on a Supelco Discovery C18 (4.6 mm × 50 mm, 5.0 μm) column under isocratic condition using 0.0 1M ammonium acetate (pH 4.5):acetonitrile (10:90, v/v) as a mobile phase. The mobile phase was delivered at a flow rate of 0.8 mL/min. The method was proved to be accurate and precise at linearity range of 0.78-200 ng/mL with a correlation coefficient (r) of ≥ 0.996. The intra- and inter-day assay precision ranged from 1.89 to 8.54% and 3.97 to 10.26%, respectively; and intra- and inter-day assay accuracy was between 87.63 and 109.06% and 96 and 103.89%, respectively for both the analytes. The method was successfully applied to study the effect of oral co-administration of BCA (an isoflavone) on the pharmacokinetics of tamoxifen and 4-hydroxytamoxifen in female rats. The coadministration of BCA caused no significant changes in the pharmacokinetics of tamoxifen and 4-hydroxytamoxifen. However, the peak plasma concentration (C(max)) of 4-hydroxytamoxifen in BCA pretreated rats was significantly (P<0.05) lower than those from control group.
他莫昔芬是治疗雌激素受体阳性乳腺癌的首选药物。他莫昔芬是 P-糖蛋白（P-gp）和细胞色素 P450（CYP）3A 的底物，而大豆黄素（BCA）是 P-gp 和 CYP3A 的抑制剂。因此，可以预期 BCA 会影响他莫昔芬的药代动力学。在本研究中，我们开发并验证了一种简单、灵敏和特异的 LC-ESI-MS/MS 方法，用于同时定量分析 100μL 大鼠血浆中的他莫昔芬及其代谢物 4-羟基他莫昔芬，以 centchroman 为内标（IS）。他莫昔芬、4-羟基他莫昔芬和 IS 采用 Supelco Discovery C18（4.6mm×50mm，5.0μm）柱，在等度条件下，以 0.01M 乙酸铵（pH4.5）：乙腈（10：90，v/v）为流动相进行分离。流动相以 0.8mL/min 的流速输送。该方法在 0.78-200ng/mL 的线性范围内具有准确性和精密度，相关系数（r）≥0.996。日内和日间测定的精密度范围分别为 1.89%-8.54%和 3.97%-10.26%；日内和日间测定的准确度分别为 87.63%-109.06%和 96%-103.89%。该方法成功应用于研究口服大豆黄素（一种异黄酮）对雌性大鼠他莫昔芬和 4-羟基他莫昔芬药代动力学的影响。BCA 的共同给药对他莫昔芬和 4-羟基他莫昔芬的药代动力学没有显著影响。然而，BCA 预处理大鼠中 4-羟基他莫昔芬的血浆峰浓度（C（max））明显（P<0.05）低于对照组。
