基于多西他赛药物性肝损伤和异甘草酸镁保肝双向机制的药动/毒效/药效关联研究及临床转化外推

Docetaxel, as a tubulin inhibitor, exhibited definite antitumor efficacy, but it would induce liver injury in patients inevitably. Magnesium isoglycyrrhizinate showed prominent hepatoprotective effects in clinical, and had a wide prospect in treating drug-induced liver injury. This application systematically described the characteristics of docetaxel induced liver injury based on docetaxel’s limitation in clinical to further elucidate the mechanism of liver injury based on the bile acid treatment, mitochondrial oxidative phosphorylation and oxidative stress pathways. This application investigated the effect of magnesium isoglycyrrhizinate on docetaxel induced liver injury to deeply elucidate the hepatoprotective mechanism of magnesium isoglycyrrhizinate from molecular, cellular and animal levels on the basis of the mechanism of docetaxel induced liver injury. Afterwards, the pharmacokinetic / toxicity / efficacy correlation model was established based on the bile acid treatment, mitochondrial oxidative phosphorylation and oxidative stress mechanism to analyze the relationship of time course profiles between docetaxel induced liver injury and magnesium isoglycyrrhizinate’s hepatoproctective effects. The non-clinical relevant model was used to describe the interspecies and in vitro/vivo transformations based on quantitative pharmacology transformation to obtain clinical pharmacokinetic / pharmacodynamic parameters, therefore quantitatively evaluated the dose/ concentration/ toxicity/ efficacy relationships between docetaxel induced liver injury and magnesium isoglycyrrhizinate’s hepatoproctective effects. This application prospectively predicted the developments of docetaxel induced liver injury in clinical, guiding the clinical regimen of magnesium isoglycyrrhizinate.

多西他赛作为微管蛋白抑制剂抗肿瘤疗效确切，但同时也会引起患者药物性肝损伤。异甘草酸镁是目前临床上疗效明确的保肝药物，治疗药物性肝损伤的应用前景广泛。本申请书系统分析了多西他赛药物性肝损伤的发生发展特点和异甘草酸镁对多西他赛诱导的肝损伤保肝药效，并且基于胆汁酸处置、线粒体氧化磷酸化及氧化应激通路从分子、细胞和动物水平阐明肝损伤毒性机制和保肝药效机制。在上述基础上采用数据模型的方法建立基于多西他赛毒性机制和异甘草酸镁保肝机制的药动/毒效/药效关联模型，分析荷瘤小鼠多西他赛药物性肝损伤和异甘草酸镁保肝作用的时程变化规律。最后利用定量药理学转化方法将建立的非临床药动/毒效/药效关联模型进行种属间和体内外转化获得临床关联模型，量化多西他赛肝损伤和异甘草酸镁保肝作用的剂量-浓度-毒效-药效关系，前瞻性地预测临床多西他赛肝损伤的发生发展规律，指导异甘草酸镁的临床保肝治疗方案。

本研究系统地阐释了抗肿瘤细胞毒药物肝损毒性作用及机制和异甘草酸镁保肝作用及机制，为深入了解抗肿瘤细胞毒药物性肝损伤病理基础和异甘草酸镁保肝药效特点提供理论和实验依据。 基于药物生理机制处置、胆汁酸蓄积、氧化应激和线粒体氧化磷酸化机制建立药物肝损伤剂量-毒效-药效的定量药理学关系，阐释抗肿瘤细胞毒药物肝损毒性规律及异甘草酸镁治疗特点，为预判药物性肝损伤和制定治疗方案提供模型参数。基于定量药理学转化思路，将抗肿瘤细胞毒药物和异甘草酸镁非临床剂量-浓度-毒效-药效模型参数进行临床转化，突破种属间和体内外转化障碍，获得临床剂量-浓度-毒效-药效模型参数，仿真预测临床患者药物性肝损伤的发生和治疗效果。