Vlasia Kastrinou-Lampou, Raquel Rodríguez-Pérez, Birk Poller, Felix Huth, Zsuzsanna Gáborik, Beáta Mártonné-Tóth, Csilla Temesszentandrási-Ambrus, Heiko S. Schadt, Gerd A. Kullak-Ublick, Michael Arand, Gian Camenisch
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引用次数: 0
摘要
肝脏胆汁酸调节是一个由多种肝脏转运体和酶调节的多方面过程。药物性胆汁淤积症(DIC)是药物性肝损伤(DILI)的一种主要类型,是指任何药物介导的肝脏胆汁流动受损的情况。目前,我们将临床前毒理学研究结果转化为人类 DIC 风险的能力非常有限,这主要是由于物种间存在重大差异。因此,由于胆汁酸平衡的复杂性,利用现有的体外或硅学模型预测临床 DIC 也具有挑战性。在此,我们评估了 47 种已上市药物的体外抑制潜力,这些药物的 DILI 严重程度各不相同,它们对目前已知参与肝脏胆汁酸调节的所有代谢和转运机制都有抑制作用。报告的 DILI 关注度和/或胆汁淤积注释与被抑制的研究过程数量相关。此外,我们还采用了单变量和多变量统计方法来确定鉴别 DILI 的重要过程。我们发现细胞色素 P450 (CYP) 3A4 的时间依赖性抑制 (TDI) 和有机阴离子转运多肽 (OATP) 1B1 的可逆性抑制是胆汁酸转运和代谢相关机制中 DIC 的主要风险因素。这些结果在我们数据集中应用的多种统计方法和 DILI 分类系统中都是一致的。我们预计,我们对胆汁淤积症发生过程中两个最重要环节的评估将使 DIC 风险评估有效地融入临床前开发过程。
Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC)
Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.
期刊介绍:
Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.