Department of Pharmacy, Groupement Hospitalier Nord, Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69317, Lyon Cedex 04, France,
Clin Pharmacokinet. 2014 Jun;53(6):521-32. doi: 10.1007/s40262-014-0146-1.
Kidney disease not only alters the renal elimination but also the non-renal disposition of drugs that are metabolized by the liver. Indeed, modifications in the expression and activity of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Accumulated uremic toxins, inflammatory cytokines, and parathyroid hormones may modulate these proteins either directly or by inhibiting gene expression. This can lead to important unintended variations in exposure and response when drugs are administered without dose adjustment for reduced renal function. This review summarizes our current understanding of non-renal clearance in circumstances of chronic and acute renal failure with experimental but also clinical studies. It also evaluates the clinical impact on drug disposition. Predicting the extent of the drug disposition modification is difficult first because of the complex interplay between metabolic enzymes and transport proteins but also because of the differential effects in the different organs (liver, intestines). Recommendations of the US FDA are presented as they may be potentially helpful tools to predict these modifications when no specific pharmacokinetic studies are available.
肾脏疾病不仅改变了肾脏对药物的排泄，也改变了肝脏代谢的药物的非肾处置。事实上，已经报道了肠道和肝脏药物代谢酶以及摄取和外排转运体的表达和活性的改变。蓄积的尿毒症毒素、炎症细胞因子和甲状旁腺激素可能通过直接或抑制基因表达来调节这些蛋白。当不根据肾功能降低调整药物剂量而给药时，这可能导致暴露和反应的重要非预期变化。本综述总结了我们目前对慢性和急性肾衰竭情况下非肾清除的理解，包括实验和临床研究。它还评估了对药物处置的临床影响。首先，由于代谢酶和转运蛋白之间的复杂相互作用，以及在不同器官（肝脏、肠道）中的不同影响，预测药物处置改变的程度非常困难。本文还介绍了美国 FDA 的建议，因为在没有特定药代动力学研究的情况下，这些建议可能是预测这些改变的有用工具。
