Liu Xin, Shang Junmei, Fu Qiang, Lu Lin, Deng Jianhua, Tang Yan, Li Jiantao, Mei Dan, Zhang Bo, Zhang Shuyang
Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
Front Oncol. 2022 Jun 30;12:919027. doi: 10.3389/fonc.2022.919027. eCollection 2022.
Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00-22.50) with a median dose of 2 g/day (2.00-2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.
米托坦是唯一被批准用于治疗肾上腺皮质癌（ACC）的药物，其药代动力学/药效学关系已得到明确。然而，关于影响米托坦药代动力学个体间巨大差异的因素的证据有限。为解决这一问题，对接受米托坦治疗超过3个月的中国ACC患者进行了一项回顾性分析。在稳态时检测米托坦血浆谷浓度，并对细胞色素P450 2B6（CYP2B6）、细胞色素P450 3A4（CYP3A4）和孕烷X受体（PXR）多态性进行基因分型。在检查了同质药理学数据后，我们将分析限制在36例接受米托坦治疗的患者，这些患者的中位（四分位间距，IQR）治疗时间为9个月（5.00 - 22.50），中位剂量为2克/天（2.00 - 2.50）。结果显示，米托坦的累积剂量对药物暴露有显著影响，CYP2B6 516GG和CYP2B6 26570CC处于米托坦治疗范围以下的高风险状态。未发现米托坦浓度与CYP3A4或PXR多态性之间存在关联。我们的数据首次表明，米托坦的累积剂量以及CYP2B6 516和CYP2B6 26570的多态性可能会显著影响中国ACC患者的米托坦血浆谷浓度。
