Liabeuf Sophie, Berdougo-Tritz Jessica, Augey Lucie, Mbarek Aïcha, Jadoul Michel, Deray Gilbert, Massy Ziad A
Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Hospital, Amiens, France.
MP3CV Laboratory, Jules Verne University of Picardie, Amiens, France.
Fundam Clin Pharmacol. 2025 Aug;39(4):e70037. doi: 10.1111/fcp.70037.
Chronic kidney disease (CKD) affects over 10% of the world's population and is associated with high morbidity and mortality rates. The management of CKD is complex; CKD alters drug pharmacokinetics and pharmacodynamics and further complicates therapeutic strategies regimens. Uremic toxins accumulate in patients with CKD and significantly impact drug pharmacokinetics and drug responses. These toxins modify drug pharmacokinetics. Indeed, uremic toxins can alter intestinal absorption by affecting drug transporters, such as P-glycoprotein and multidrug resistance-associated proteins. These changes modify the bioavailability of drugs and change drug absorption profiles in patients with CKD. Furthermore, uremic toxins interfere with drug distribution and metabolism. For instance, the urea-driven carbamylation of albumin can reduce drug-binding sites on this plasma protein and thus increase the free drug fraction. In the liver, CKD can reduce the expression of cytochrome P450 enzymes and thus impair drug biotransformation. Furthermore, uremic toxins can interact with cellular transporters, affecting drug clearance and leading to drug accumulation. In terms of pharmacodynamics, uremic toxins can alter receptor function and impair drug effectiveness. The blood-brain barrier may also be disrupted by the accumulation of toxins; this enhances drug penetration into the brain and increases the risk of adverse effects. After providing a brief summary of the various drug elimination pathways and the definitions and classification of uremic toxins, we shall use examples to illustrate the potential impact of a decrease in glomerular filtration rate (GFR) and/or an increase in uremic toxin levels on drug pharmacokinetics and pharmacodynamics.
慢性肾脏病（CKD）影响着全球超过10%的人口，且与高发病率和死亡率相关。CKD的管理很复杂；CKD会改变药物的药代动力学和药效学，并使治疗策略方案进一步复杂化。尿毒症毒素在CKD患者体内蓄积，对药物药代动力学和药物反应有显著影响。这些毒素会改变药物药代动力学。事实上，尿毒症毒素可通过影响药物转运体（如P-糖蛋白和多药耐药相关蛋白）来改变肠道吸收。这些变化会改变药物的生物利用度，并改变CKD患者的药物吸收情况。此外，尿毒症毒素会干扰药物分布和代谢。例如，尿素驱动的白蛋白氨甲酰化可减少这种血浆蛋白上的药物结合位点，从而增加游离药物分数。在肝脏中，CKD可降低细胞色素P450酶的表达，从而损害药物生物转化。此外，尿毒症毒素可与细胞转运体相互作用，影响药物清除并导致药物蓄积。在药效学方面，尿毒症毒素可改变受体功能并损害药物疗效。毒素的蓄积也可能破坏血脑屏障；这会增强药物向脑内的渗透并增加不良反应的风险。在简要总结了各种药物消除途径以及尿毒症毒素的定义和分类后，我们将通过实例来说明肾小球滤过率（GFR）降低和/或尿毒症毒素水平升高对药物药代动力学和药效学的潜在影响。
