Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261, USA.
Adv Chronic Kidney Dis. 2010 Sep;17(5):384-91. doi: 10.1053/j.ackd.2010.05.009.
Patients with chronic kidney disease (CKD) represent a significant and growing segment of the US population. A mounting body of experimental and clinical evidence indicates that nonrenal drug clearance is altered in patients with CKD. Specific nonrenal clearance (CL(NR)) pathways that are affected have been identified in experimental models, and include cytochrome P450 enzymes, P-glycoprotein, and organic anion-transporting polypeptides. Altered CL(NR) of several drugs has been described in clinical pharmacokinetics studies, but to date the specific CL(NR) pathways that are affected in CKD patients and result in clinically significant changes in drug exposure have not been definitively established, and the mechanism has not been elucidated. Accumulated uremic toxins may downregulate or directly inhibit drug metabolism and transport pathways, and may do so in a reversible manner. Future Food and Drug Administration recommendations pertaining to the conduct of pharmacokinetic studies in CKD will undoubtedly facilitate the search for the CL(NR) path less traveled, clarify the mechanisms involved, improve our understanding of the clinical significance of altered CL(NR) of individual drugs, and lead to more comprehensive drug dosing recommendations for patients with CKD. This review summarizes our current understanding of this field, focusing on recent developments in the search for the CL(NR) "path less traveled" in CKD.
患有慢性肾病（CKD）的患者在美国人群中占有相当大的比例，且呈不断增长的趋势。越来越多的实验和临床证据表明，CKD 患者的非肾脏药物清除率发生了改变。在实验模型中已经确定了受影响的特定非肾脏清除（CL（NR））途径，包括细胞色素 P450 酶、P-糖蛋白和有机阴离子转运多肽。在临床药代动力学研究中已经描述了几种药物的 CL（NR）改变，但迄今为止，尚未明确确定 CKD 患者中受影响的特定 CL（NR）途径以及导致药物暴露发生临床显著变化的途径，并且其机制尚未阐明。蓄积的尿毒症毒素可能下调或直接抑制药物代谢和转运途径，而且这种抑制可能是可逆的。未来食品和药物管理局关于 CKD 药代动力学研究的建议无疑将有助于寻找未走过的 CL（NR）途径，阐明相关机制，提高我们对个体药物 CL（NR）改变的临床意义的理解，并为 CKD 患者提供更全面的药物剂量建议。这篇综述总结了我们对这一领域的现有理解，重点介绍了在寻找 CKD 中未走过的 CL（NR）途径方面的最新进展。
