Kong Weijie, Pan Yuejuan, Wu Yujie, Hu Yiyi, Jiang Zhenbin, Tian Xinkui, Bi Shuhong, Wang Song, Feng Feifei, Jin Yuyan, Li Jiayu, Li Haiyan, Wang Yue, Liang Hao, Tang Wen, Liu Dongyang
Department of Nephrology, Peking University Third Hospital, Beijing, China.
Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
Clin Pharmacol Ther. 2025 May;117(5):1303-1312. doi: 10.1002/cpt.3546. Epub 2025 Jan 10.
OATP1B, P-gp, BCRP, and CYP3A are the most contributing drug-metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end-stage renal disease (ESRD) patients with large inter-individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8-, 3.1-, 1.1-, and 1.3-fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus Veillonella and Clostridium_XIVb were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P-gp activity decreased by 35-75% and 29-44%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.
OATP1B、P-糖蛋白、乳腺癌耐药蛋白（BCRP）和细胞色素P450 3A（CYP3A）是常用处方药中最主要的药物代谢酶或转运蛋白（药物代谢酶和转运蛋白，DMETs）。在终末期肾病（ESRD）患者中，它们的活性可能会发生变化，个体间存在较大差异（IIVs），导致底物药物暴露改变，最终增加安全风险。然而，到目前为止，变化程度和指示性影响因素尚未量化。在此，将含有五种针对这些DMETs的敏感底物药物（匹伐他汀、达比加群酯、瑞舒伐他汀、咪达唑仑和阿托伐他汀）的微剂量鸡尾酒方案给予中国健康志愿者和ESRD患者。测定了药物药代动力学特征以及生理、药物遗传学和肠道微生物组特征。建立了群体药代动力学和机器学习模型，以确定关键影响因素并量化它们对药物暴露变化的贡献。在ESRD患者中，匹伐他汀、达比加群、瑞舒伐他汀和阿托伐他汀的暴露分别增加到1.8倍、3.1倍、1.1倍和1.3倍，而咪达唑仑暴露减少了72%。值得注意的是，除了疾病状态外，首先确定韦荣球菌属和梭菌属_XIVb的相对丰度分别是匹伐他汀和瑞舒伐他汀表观清除率的显著影响因素，表明它们在OATP和BCRP活性评估中的指示作用。此外，发现几个属与药物清除密切相关，并减少了无法解释的个体间差异。据此估计，OATP1B和肠道P-糖蛋白活性分别降低了35-75%和29-44%，而BCRP和CYP3A4活性可能会有所上调。我们的研究提供了对个体DMET活性的定量和机制理解，并可为ESRD患者中底物药物的精准医学提供支持。
