Cheng Yung-Yi, Zheng Teresa, Chang Michael W, Dalley Jeffrey W, Chen Yu-Jen, Tsai Tung-Hu, Hsieh Chen-Hsi
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, the University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Front Oncol. 2022 Feb 17;12:833108. doi: 10.3389/fonc.2022.833108. eCollection 2022.
The optimal procedure for combining radiotherapy (RT) with tamoxifen treatment is controversial as RT may alter the pharmacokinetics and biotransformation of tamoxifen. The present study investigated this potential interaction by assessing the pharmacokinetics of tamoxifen during concurrent and sequential RT.
Plasma tamoxifen concentration was measured in rats with or without RT 2.0 Gy (RT) or 0.5 Gy (RT) with ultra-high-performance liquid chromatography-tandem mass spectrometry after tamoxifen administration (10 mg/kg, p.o., = 6). Tamoxifen was either administered 1 h after RT (concurrent condition) or 24 h after RT (sequential condition).
Pharmacokinetic data analysis demonstrated that the area under the curve (AUC) and half-life of tamoxifen were 2,004 ± 241 h ng/ml and 6.23 ± 1.21 h, respectively, after tamoxifen administration (10 mg/kg, p.o.). The respective conversion rate of 4-hydroxytamoxifen, -desmethytamoxifen, and endoxifen for tamoxifen metabolism was 20%, 16%, and 5%. The AUC value of tamoxifen in the RT group was 1.5- to 1.7-fold higher than in the sham and RT groups. The relative bioavailability of tamoxifen at concurrent RT and RT groups ranged from 127% to 202% and from 71% to 152%, respectively. The magnitude of endoxifen, which converted from 4-hydroxytamoxifen and -desmethyltamoxifen, increased 3- to 5-fold in the concurrent RT groups. By contrast, the AUC of tamoxifen decreased by roughly 24% in the sequential RT group. The conversion ratio of endoxifen was four times higher than that in the sequential RT group compared with rats not exposed to RT.
The current study provides advanced pharmacokinetic data to confirm the interaction between RT and hormone therapy. Our findings indicate that RT facilitates the metabolism of tamoxifen to active metabolites and thus imply that combination RT-tamoxifen has potential benefits for the treatment of hormone-dependent breast cancer.
放疗（RT）与他莫昔芬联合治疗的最佳方案存在争议，因为放疗可能会改变他莫昔芬的药代动力学和生物转化。本研究通过评估同步和序贯放疗期间他莫昔芬的药代动力学来研究这种潜在的相互作用。
在给予他莫昔芬（10mg/kg，口服，n = 6）后，用超高效液相色谱-串联质谱法测量接受或未接受2.0Gy（RT）或0.5Gy（RT）放疗的大鼠血浆中他莫昔芬的浓度。他莫昔芬在放疗后1小时（同步条件）或放疗后24小时（序贯条件）给药。
药代动力学数据分析表明，给予他莫昔芬（10mg/kg，口服）后，他莫昔芬的曲线下面积（AUC）和半衰期分别为2,004±241h ng/ml和6.23±1.21h。他莫昔芬代谢产物4-羟基他莫昔芬、N-去甲基他莫昔芬和内昔芬的各自转化率分别为20%、16%和5%。放疗组中他莫昔芬的AUC值比假手术组和RT组高1.5至1.7倍。同步放疗组和RT组中他莫昔芬的相对生物利用度分别为127%至202%和71%至152%。在同步放疗组中，由4-羟基他莫昔芬和N-去甲基他莫昔芬转化而来的内昔芬量增加了3至5倍。相比之下，序贯放疗组中他莫昔芬的AUC大约降低了24%。与未接受放疗的大鼠相比，序贯放疗组中内昔芬的转化率高出四倍。
本研究提供了先进的药代动力学数据，以证实放疗与激素治疗之间的相互作用。我们的研究结果表明，放疗促进他莫昔芬代谢为活性代谢产物，因此意味着放疗与他莫昔芬联合应用对激素依赖性乳腺癌的治疗具有潜在益处。
