Asim Ashna, Wang Fen, Pu Dong, Wang Sisi, Wang Dian, Li Wenwen, Yu Feng, Ji Li
Department of Clinical Pharmacy, China Pharmaceutical University, School of Basic Medicine and Clinical Pharmacy, Nanjing, China.
Department of Clinical Pharmacy, Yifu Hospital, Nanjing Medical University, Nanjing, China.
Balkan Med J. 2025 Jan 2;42(1):37-44. doi: 10.4274/balkanmedj.galenos.2024.2024-9-12.
In uremic patients, the accumulation of gut-derived protein-bound uremic toxins (PBUTs) induces changes in the microenvironment of the patients, leading to changes in the elimination pattern of drugs.
To assess ways in which PBUTs alter the CYP450 enzymes in hepatocytes as well as the possible effects of specific PBUTs on the metabolism and excretion of atorvastatin (ATV).
An experimental study.
The experimental group was treated with long-term MHD for > 3 months, estimated-glomerular filtration rate (e-GFR) < 15 ml/min, normal Alb level (35.0-55.0 g/l), and no urine; the control group was not treated with hemodialysis, e-GFR < 60 ml/min, normal Alb level, and normal urinary excretion function. A suitable UPLC-MS/MS method was developed for detecting the concentration of 4-hydroxy ATV. Fresh primary hepatocytes were isolated from rats, and the uptake of ATV was tested in the uremic serum (US) group, IS group, and HA group and compared with that in the normal serum group. The metabolic status of ATV in the US group, IS group, and HA group was compared with that in the ATV group. RLM were extracted, and the metabolic experiment of ATV was performed in a human CYP3A4 model. The influence of UTs on pregnane X receptor (PXR)/nuclear factor kappa B (NF-κB) mRNA and the protein expression was also detected.
IS and HA inhibited the ATV metabolism to varying degrees, wherein IS was the most potent inhibitor, producing > 50% inhibition. Meanwhile, the protein expression of CYP3A4 was downregulated after incubation with US, IS, and HA ( < 0.01). The excretion of ATV was also inhibited by 59.24% and 71.95% after incubation with IS and HA, respectively. The effects of uremic toxins on PXR/NF-κB mRNA and protein expression elucidated that PBUTs can inhibit ATV uptake and metabolism by exerting inhibitory effects on CYP3A4 through the PXR/NF-κB signaling pathway.
ATV metabolism could be significantly altered in the presence of uremic toxins, suggesting a downregulated effect on the ATV uptake, possibly through Oatp1b1, and also on the activity of CYP3A4 through the PXR/NF-κB signaling pathway.
在尿毒症患者中，肠道来源的蛋白结合尿毒症毒素（PBUTs）的蓄积会引起患者微环境的变化，从而导致药物消除模式的改变。
评估PBUTs改变肝细胞中CYP450酶的方式以及特定PBUTs对阿托伐他汀（ATV）代谢和排泄的可能影响。
一项实验研究。
实验组接受长期维持性血液透析（MHD）超过3个月，估计肾小球滤过率（e-GFR）<15 ml/min，白蛋白（Alb）水平正常（35.0 - 55.0 g/l），且无尿；对照组未接受血液透析，e-GFR<60 ml/min，Alb水平正常，且尿排泄功能正常。开发了一种合适的超高效液相色谱-串联质谱（UPLC-MS/MS）方法来检测4-羟基阿托伐他汀的浓度。从大鼠中分离新鲜的原代肝细胞，在尿毒症血清（US）组、炎症血清（IS）组和高尿酸血症（HA）组中测试阿托伐他汀的摄取，并与正常血清组进行比较。比较US组、IS组和HA组中阿托伐他汀的代谢状态与阿托伐他汀组的代谢状态。提取大鼠肝微粒体（RLM），并在人CYP3A4模型中进行阿托伐他汀的代谢实验。还检测了尿毒症毒素对孕烷X受体（PXR）/核因子κB（NF-κB）mRNA和蛋白表达的影响。
IS和HA不同程度地抑制了阿托伐他汀的代谢，其中IS是最有效的抑制剂，抑制率>50%。同时，与US、IS和HA孵育后，CYP3A4的蛋白表达下调（<0.01）。与IS和HA孵育后，阿托伐他汀的排泄也分别被抑制了59.24%和71.95%。尿毒症毒素对PXR/NF-κB mRNA和蛋白表达的影响表明，PBUTs可通过PXR/NF-κB信号通路对CYP3A4发挥抑制作用，从而抑制阿托伐他汀的摄取和代谢。
在存在尿毒症毒素的情况下，阿托伐他汀的代谢可能会发生显著改变，这表明可能通过Oatp1b1下调阿托伐他汀的摄取，并通过PXR/NF-κB信号通路下调CYP3A4的活性。
