Ladda Matthew A, Goralski Kerry B
College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada; and Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada; and Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Adv Chronic Kidney Dis. 2016 Mar;23(2):67-75. doi: 10.1053/j.ackd.2015.10.002.
CKD affects a significant proportion of the world's population, and the prevalence of CKD is increasing. Standard practice currently is to adjust the dose of renally eliminated medications as kidney function declines in effort to prevent adverse drug reactions. It is increasingly becoming recognized that CKD also impacts nonrenal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport proteins, the latter of which is beyond the scope of this review. CYPs are responsible for the metabolism of many clinically used drugs. Genetics, patient factors (eg, age and disease) and drug interactions are well known to affect CYP metabolism resulting in variable pharmacokinetics and responses to medications. There now exists an abundance of evidence demonstrating that CKD can impact the activity of many CYP isoforms either through direct inhibition by circulating uremic toxins and/or by reducing CYP gene expression. Evidence suggests that reductions in CYP metabolism in ESRD are reversed by kidney transplantation and temporarily restored via hemodialysis. This review summarizes the current understanding of the effects that CKD can have on CYP metabolism and also discusses the impact that CYP metabolism phenotypes can have on the development of kidney injury.
慢性肾脏病（CKD）影响着世界上很大一部分人口，且CKD的患病率正在上升。目前的标准做法是随着肾功能下降调整经肾脏消除的药物剂量，以预防药物不良反应。人们越来越认识到，CKD也会影响非肾脏清除机制，如肝脏和肠道的细胞色素P450（CYP）酶以及药物转运蛋白，后者不在本综述范围内。细胞色素P450酶负责许多临床常用药物的代谢。众所周知，基因、患者因素（如年龄和疾病）以及药物相互作用会影响细胞色素P450酶的代谢，从而导致药代动力学和药物反应的差异。现在有大量证据表明，CKD可通过循环中的尿毒症毒素直接抑制和/或通过降低细胞色素P450酶基因表达来影响多种细胞色素P450同工酶的活性。有证据表明，终末期肾病（ESRD）中细胞色素P450酶代谢的降低可通过肾移植逆转，并通过血液透析暂时恢复。本综述总结了目前对CKD对细胞色素P450酶代谢影响的认识，并讨论了细胞色素P450酶代谢表型对肾损伤发生发展的影响。
