El-Khateeb Eman, Achour Brahim, Al-Majdoub Zubida M, Barber Jill, Rostami-Hodjegan Amin
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester M13 9PT, U.K.
Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
Mol Pharm. 2021 Sep 6;18(9):3563-3577. doi: 10.1021/acs.molpharmaceut.1c00462. Epub 2021 Aug 24.
Liver cirrhosis is a chronic disease that affects the liver structure, protein expression, and overall metabolic function. Abundance data for drug-metabolizing enzymes and transporters (DMET) across all stages of disease severity are scarce. Levels of these proteins are crucial for the accurate prediction of drug clearance in hepatically impaired patients using physiologically based pharmacokinetic (PBPK) models, which can be used to guide the selection of more precise dosing. This study aimed to experimentally quantify these proteins in human liver samples and assess how they can impact the predictive performance of the PBPK models. We determined the absolute abundance of 51 DMET proteins in human liver microsomes across the three degrees of cirrhosis severity ( = 32; 6 mild, 13 moderate, and 13 severe), compared to histologically normal controls ( = 14), using QconCAT-based targeted proteomics. The results revealed a significant but non-uniform reduction in the abundance of enzymes and transporters, from control, by 30-50% in mild, 40-70% in moderate, and 50-90% in severe cirrhosis groups. Cancer and/or non-alcoholic fatty liver disease-related cirrhosis showed larger deterioration in levels of CYP3A4, 2C8, 2E1, 1A6, UGT2B4/7, CES1, FMO3/5, EPHX1, MGST1/3, BSEP, and OATP2B1 than the cholestasis set. Drug-specific pathways together with non-uniform changes of abundance across the enzymes and transporters under various degrees of cirrhosis necessitate the use of PBPK models. As case examples, such models for repaglinide, dabigatran, and zidovudine were successful in recovering disease-related alterations in drug exposure. In conclusion, the current study provides the biological rationale behind the absence of a single dose adjustment formula for all drugs in cirrhosis and demonstrates the utility of proteomics-informed PBPK modeling for drug-specific dose adjustment in liver cirrhosis.
肝硬化是一种影响肝脏结构、蛋白质表达及整体代谢功能的慢性疾病。关于疾病严重程度各阶段药物代谢酶和转运体（DMET）的丰度数据稀缺。这些蛋白质的水平对于使用基于生理的药代动力学（PBPK）模型准确预测肝功能受损患者的药物清除率至关重要，该模型可用于指导更精确给药方案的选择。本研究旨在通过实验对人肝脏样本中的这些蛋白质进行定量，并评估它们如何影响PBPK模型的预测性能。我们使用基于QconCAT的靶向蛋白质组学方法，测定了32例不同程度肝硬化严重程度（6例轻度、13例中度和13例重度）的人肝脏微粒体中51种DMET蛋白质的绝对丰度，并与14例组织学正常的对照进行比较。结果显示，与对照组相比，酶和转运体的丰度显著但不均匀地降低，轻度肝硬化组降低30 - 50%，中度肝硬化组降低40 - 70%，重度肝硬化组降低50 - 90%。与癌症和/或非酒精性脂肪性肝病相关的肝硬化在CYP3A4、2C8、2E1、1A6、UGT2B4/7、CES1、FMO3/5、EPHX1、MGST1/3、BSEP和OATP2B1水平上的恶化程度比胆汁淤积组更大。药物特异性途径以及不同程度肝硬化下酶和转运体丰度的不均匀变化使得有必要使用PBPK模型。作为实例，瑞格列奈、达比加群和齐多夫定的此类模型成功地恢复了与疾病相关的药物暴露变化。总之，本研究为肝硬化患者并非所有药物都有单一剂量调整公式提供了生物学依据，并证明了蛋白质组学信息指导的PBPK模型在肝硬化患者药物特异性剂量调整中的实用性。
